Prediction of schizophrenia risk using homozygous genetic markers

ABSTRACT

Provided are methods of identifying a genetic profile influencing the relative probability of a subject manifesting a phenotype that is at least partially heritable. Also provided are methods of determining the relative likelihood that a subject will manifest a phenotype that is at least partially heritable. Additionally, methods of determining the relative risk of a human subject for manifesting schizophrenia are provided. Further provided are methods of screening a human embryo in vitro for the risk of becoming a human manifesting schizophrenia. Also, methods of identifying a single nucleotide polymorphism (SNP) variant affecting the risk of a human subject for manifesting schizophrenia are provided. Methods of screening for a compound that may affect schizophrenia are additionally provided.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This application claims the benefit of U.S. Provisional PatentApplication No. 60/934,728 filed on Jun. 15, 2007, the contents of whichare hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was supported by NIH grants MH065580, MH074543, andMH001760. As such, the U.S. Government has certain rights in thisinvention.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention generally relates to prediction of disease risk.More specifically, the invention is directed to methods of identifying adisease risk genotype. The invention is also directed to methods fordetermining the relative risk of manifesting schizophrenia.

(2) Description of the Related Art

The recent development of microarray platforms, capable of genotypinghundreds of thousands of single nucleotide polymorphisms (SNPs), hasprovided an opportunity to rapidly identify novel susceptibility genesfor complex phenotypes. Studies employing genotyping microarrays havetypically utilized a whole genome association (WGA) approach, in whicheach SNP is examined individually for association with disease(Hirschhorn and Daly, 2005); multiple testing requires that statisticalthresholds for WGA approach 10⁻⁷ or lower (Carlson et al., 2004). Giventhe presumably polygenic nature of complex illness, this conservativestrategy inevitably results in false negatives in the search forsusceptibility genes (Storey and Tibshirani, 2003).

Schizophrenia (SCZ) is a disease with estimated lifetime morbid riskapproaching 1% worldwide. Although genetic epidemiologic studies haverevealed high heritability estimates (70-80%) for SCZ, identification ofsusceptibility genes remains challenging. As with other complexdiseases, linkage studies have revealed multiple candidate regions withmodest LOD scores (Lewis et al., 2003), while studies of individualcandidate genes are inherently limited in scope.

In light of the above, improved methods for identifying disease(especially SCZ) susceptibility loci are needed. The present inventionaddresses that need.

SUMMARY OF THE INVENTION

The inventors have developed a method for identifying genetic lociinfluencing a heritable phenotype. The method utilizes theidentification of long runs of consecutive SNP loci that are homozygous,where these “runs of homozygosity” (ROH) are associated with theoccurrence of the phenotype. This invention was validated by identifyingROH associated with schizophrenia.

The present invention is directed to methods of identifying a geneticprofile influencing the relative probability of a subject manifesting aphenotype that is at least partially heritable. The methods compriseobtaining a genomic DNA sample from each individual in two populationsof individuals, the first population consisting of individualsmanifesting the phenotype and the second population consisting ofindividuals not manifesting the phenotype; and analyzing the genomic DNAfrom each individual in the first population and the second populationto identify a run of homozygosity (ROH) present in the first populationmore often, or less often, than in the second population. An ROH presentin the first population more often than in the second populationindicates that the presence of the ROH is a genetic profile associatedwith increased probability for manifesting the phenotype, and an ROHpresent in the first population less often than in the second populationindicates that the presence of the ROH is a genetic profile associatedwith decreased probability for manifesting the phenotype. With thesemethods, an ROH is a series of consecutive known single nucleotidepolymorphism (SNP) positions that are homozygous in the genome of anindividual.

The invention is also directed to methods of determining the relativelikelihood that a subject will manifest a phenotype. The methodscomprise determining whether the subject has a genetic profileassociated with an increased likelihood for manifesting the phenotype.The genetic profile is identified by the method described above. Inthese methods, a subject having the genetic profile has an increasedlikelihood of manifesting the phenotype over a subject not having thegenetic profile.

Additionally, the invention is directed to methods of determining therelative risk of a human subject for manifesting schizophrenia. Themethods comprise determining the presence of a first run of homozygosity(ROH) in the genome of the subject, where the presence of the first ROHindicates the subject has an increased risk for manifestingschizophrenia over a subject not having the first ROH. In these methods,the first ROH is a series of consecutive single nucleotide polymorphism(SNP) positions that are homozygous in the subject from one of roh250,roh321, roh314, roh52, roh15, roh129, roh291, roh55, or roh173 asdefined in Table 2.

The invention is further directed to other methods of determining therelative risk of a human subject for manifesting schizophrenia. Themethods comprise determining whether the subject has a run ofhomozygosity (ROH) that contains at least 80% of the SNPs in at leastone of the three locations identified in Supplementary Table 2 ascorrelated with schizophrenia. A subject having an ROH that contains atleast 80% of the SNPs in at least one of the three locations identifiedin Supplementary Table 2 has an increased risk for manifestingschizophrenia over a subject not having such an ROH.

Also, the invention is directed to methods of screening a human embryoin vitro for the risk of becoming a human manifesting schizophrenia. Themethods comprise determining the presence of a first run of homozygosity(ROH) in the genome of the embryo, where the presence of the first ROHindicates the embryo has an increased risk for manifesting schizophreniaover an embryo not having the first ROH. Here, the first ROH is a seriesof consecutive single nucleotide polymorphism (SNP) positions that arehomozygous in the subject from one of roh250, roh321, roh314, roh52,roh15, roh129, roh291, roh55, or roh173 as defined in Table 2.

The invention is additionally directed to methods of identifying asingle nucleotide polymorphism (SNP) variant affecting the risk of ahuman subject for manifesting schizophrenia. The methods compriseidentifying a run of homozygosity (ROH) present more often in a firstpopulation of individuals having schizophrenia than in a secondpopulation of individuals not having schizophrenia, then identifying asingle nucleotide polymorphism (SNP) within the ROH or within 500 kB ofthe ROH, where a first variant of the SNP is present in the firstpopulation more often than in the second population. In these methods,the presence of the first variant of the SNP in a subject indicates thatthe subject has a greater risk for manifesting schizophrenia than theabsence of the first variant. Here, an ROH is a series of consecutiveknown SNP positions that are homozygous in the genome of an individual.

The invention is also directed to additional methods of determining therelative risk of a human subject for manifesting schizophrenia. Themethods comprise determining whether the subject has a SNP genotypeassociated with schizophrenia as identified by the method describedimmediately above. A subject with the SNP genotype has an increased riskfor manifesting schizophrenia over a subject with a different genotype.

Further, the invention is directed to methods of screening for acompound that may affect schizophrenia. The methods comprise determiningwhether the compound affects expression or activity of a gene selectedfrom the group consisting of DYNC2H1, CRHR1, IMP5, MAPT, STH, KIAA1267,LRRC37A, ARL17, LRRC37A2, WNTT3, WNT9B, GOSR2, RPRML, CDC27, CHN1,ATP5GS3, DUSP12, ATF6, OLFML2B, SGCD, MRPL22, GPHN, C14orf54, MPP5,ATP6V1D, EIF2S1, PLEK2, GULP1, DIRC1, COL3A1, COL5A2, WDR75, SLC40A1,NS3TP1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, PMS1, GDF8, IMPAD1, SNTG1 andSORCS1. Here, a compound that affects expression or activity of the genemay affect schizophrenia.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graphical depiction of statistical comparisons (SCZ vs.control) at individual SNPs within roh172 on Chromosome 8q. Chromosomalcontext is depicted in ideogram at top. Gene location (Build 35coordinates) for SNTG1 is depicted immediately below ideogram. Codingregion of SNTG1 is indicated by red dotted line; exons are indicated byhorizontal lines. Gray box depicts −log₁₀ P-values for case-controlcomparisons at each binarized SNP.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have developed a method for identifying genetic lociinfluencing a heritable phenotype. The method utilizes theidentification of long runs of consecutive SNP loci that are homozygous,where these “runs of homozygosity” (ROH) are associated with theoccurrence of the phenotype. This invention was validated by identifyingROH associated with schizophrenia. See Example.

The present invention is directed to methods of identifying a geneticprofile influencing the relative probability of a subject manifesting aphenotype that is at least partially heritable. The methods compriseobtaining a genomic DNA sample from each individual in two populationsof individuals, the first population consisting of individualsmanifesting the phenotype and the second population consisting ofindividuals not manifesting the phenotype; and analyzing the genomic DNAfrom each individual in the first population and the second populationto identify a run of homozygosity (ROH) present in the first populationmore often, or less often, than in the second population. An ROH presentin the first population more often than in the second populationindicates that the presence of the ROH is a genetic profile associatedwith increased probability for manifesting the phenotype, and an ROHpresent in the first population less often than in the second populationindicates that the presence of the ROH is a genetic profile associatedwith decreased probability for manifesting the phenotype. With thesemethods, an ROH is a series of consecutive known single nucleotidepolymorphism (SNP) positions that are homozygous in the genome of anindividual.

The “consecutive known SNP positions” that are interrogated to identifyan ROH are consecutive SNP positions that are chosen as part of themethod; this is not meant to necessarily include every consecutive SNPknown in the genome region that is being interrogated. For example, theExample describes usefully applying the invention method by using anAffymetrix gene chip that has a mean spacing of 5.8 kB between SNPs. Theskilled artisan could identify a useful collection of SNPs without undueexperimentation for any particular application of the method.

The ROH in these methods should cover a long enough stretch of thegenome, and include a sufficient number of SNP positions, to provideadequate assurance that the ROH reflects a true difference between thetwo populations. Preferably, the ROH is at least 50 kB in length. Morepreferably, the ROH is at least 100 kB in length. Even more preferably,the ROH is at least 200 kB in length. Most preferably, the ROH is atleast 500 kB in length.

The SNPs in the ROH should also occur at sufficient density such thatthere is a reasonable assurance that the presence of the consecutivehomozygous SNP positions adequately reflects the true occurrence ofpredominantly homozygous SNPs that are not interrogated in the ROH.Preferably, the consecutive known SNP positions are an average of lessthan 50 kB apart. More preferably, the consecutive known SNP positionsare an average of less than 20 kB apart. Even more preferably, theconsecutive known SNP positions are an average of less than 10 kB apart.Most preferably, the consecutive known SNP positions are an average ofless than 5 kB apart.

The density of the SNP positions and the length of the ROH determinesthe number of SNP positions covered by the ROH. Preferably, the ROH is aseries of at least 10 consecutive known SNP positions that arehomozygous. More preferably, the ROH is a series of at least 20consecutive known SNP positions that are homozygous. Even morepreferably, the ROH is a series of at least 50 consecutive known SNPpositions that are homozygous. Most preferably, the ROH is a series ofat least 100 consecutive known SNP positions that are homozygous.

The “subject” for these methods can be any mammal, including a fetus orembryo. The subject is preferably a human.

It is to be understood that the region surrounding the identified ROH(e.g., within 1000 kB on each side of the ROH, preferably 500 kB, morepreferably 200 kB, even more preferably 100 kB) is tightly linked to theROH such that the ROH could potentially be identified by identifying thegenotype at a SNP position, or a series of SNP positions (e.g.,consecutive positions) within those regions. Thus, the present methodsencompass the identification of the ROH by evaluating the genotype ofregions surrounding the identified ROH.

The ROHs identified as above that are associated with the phenotype arealso useful for identifying the SNPs that are at least partiallyresponsible for the association of the ROH with the phenotype. Such anidentification can lead to more precise and easier methods of estimatingthe relative probability that the subject will manifest the phenotype.Additionally, the association of the SNP with a genetic change in a genecould be useful for further understanding the phenotype.

Thus, in some aspects, these methods further comprise identifying allSNPs having a genotype that occurs with a different frequency in thefirst population than in the second population, then identifying anyruns of SNPs with such differences extending at least 50 consecutiveSNPs in length. In these aspects, a subject having such a run of SNPsidentical with the run in the first population has an increasedprobability for manifesting the phenotype.

The phenotype can be any trait having polygenic inheritance, includingbut not limited to characteristics relating to the development, anatomy,biochemistry or physiology of a tissue, organ or cell type, includingbut not limited to: therapeutic responses including responses to drugs,intelligence, muscle mass, presence and characteristics of immune cells,ability to produce milk, or leanness of meat. It is to be understoodthat these methods can also be used to evaluate the likely quantitativedegree that a phenotype will manifest itself in the subject.

Preferably, the disease or condition is a disease. Nonlimiting examplesinclude Parkinson's disease, Alzheimer's disease, a cancer, acardiovascular disease, an infectious disease, an autoimmune disease,and type 2 diabetes. The disease can also be a psychiatric disease.Nonlimiting examples include schizophrenia, bipolar disorder,depression, or autism. The analysis can also potentially encompassevaluation of the likelihood of achieving a particular level of severityof a disease, or rapidity of disease development.

The genetic profiles identified by the above methods can be used todetermine the likelihood that a subject with manifest the phenotype. Theinvention is thus also directed to methods of determining the relativelikelihood that a subject will manifest a phenotype. The methodscomprise determining whether the subject has a genetic profileassociated with an increased likelihood for manifesting the phenotype.The genetic profile is identified by the method described above. Inthese methods, a subject having the genetic profile has an increasedlikelihood of manifesting the phenotype over a subject not having thegenetic profile.

As discussed above, the subject being evaluated in these methods can bean adult animal or an embryo or fetus, including a human embryo orfetus, e.g., by analysis of amniotic fluid, chorionic villi. In someaspects, the subject is an embryo, in others the subject is a fetus.These methods can also be used in breeding farm or companion animals.

Preferably, the phenotype is a disease. Nonlimiting examples includeParkinson's disease, Alzheimer's disease, a cancer, a cardiovasculardisease, an infectious disease, an autoimmune disease, and type 2diabetes. The disease can also be a psychiatric disease. Nonlimitingexamples include schizophrenia, bipolar disorder, depression, or autism.The analysis can also potentially encompass evaluation of the likelihoodof the subject achieving a particular level of severity of a disease, orrapidity of disease development.

As discussed above and in the Example, the genetic profiling methoddescribed above was used to identify nine ROHs associated withschizophrenia. These ROHs are useful for evaluating the relative riskfor a human subject manifesting schizophrenia.

Thus, the invention is additionally directed to methods of determiningthe relative risk of a human subject for manifesting schizophrenia. Themethods comprise determining the presence of a first run of homozygosity(ROH) in the genome of the subject, where the presence of the first ROHindicates the subject has an increased risk for manifestingschizophrenia over a subject not having the first ROH. In these methods,the first ROH is a series of consecutive single nucleotide polymorphism(SNP) positions that are homozygous in the subject from one of roh250,roh321, roh314, roh52, roh15, roh129, roh291, roh55, or roh173 asdefined in Table 2.

Preferably, the first ROH is a series of at least 50 consecutivehomozygous SNP positions. More preferably, the first ROH is a series 100consecutive homozygous SNP positions. Most preferably, the first ROH isall of the SNP positions that are homozygous in the subject from roh250,roh321, roh314, roh52, roh15, roh129, roh291, roh55, or roh173.

Preferably, the subject is evaluated for the presence of more than oneROH. Thus, the methods preferably further comprise determining thepresence of a second ROH in the genome of the subject, where the secondROH is from one of roh250, roh321, roh314, roh52, roh15, roh129, roh291,roh55, or roh173 that is different from the first ROH. Here, thepresence of the second ROH indicates the subject has an increased riskfor manifesting schizophrenia over a subject not having the second ROH.It is preferred that the presence of roh250 is determined, since thatROH was the most strongly associated with schizophrenia.

Most preferably, the subject is evaluated for the presence of all of theROHs. Thus, preferably, wherein positions in the genome of the subjectcorresponding to each of roh250, roh321, roh314, roh52, roh15, roh129,roh291, roh55, and roh173 are evaluated for the consecutive homozygousSNP positions, wherein an increasing number of ROHs present in thesubject indicates an increasing risk in the subject for manifestingschizophrenia.

The subject in these methods can be a human adult, child, infant, fetusor embryo. In some aspects, the subject is an embryo. In others, thesubject is a fetus.

Further evaluations, as discussed in the example, led to theidentification of three additional ROHs associated with schizophrenia,described in Supplementary Table 2. The invention is thus furtherdirected to additional methods of determining the relative risk of ahuman subject for manifesting schizophrenia. The methods comprisedetermining whether the subject has a run of homozygosity (ROH) thatcontains at least 80% of the SNPs in at least one of the three locationsidentified in Supplementary Table 2 as correlated with schizophrenia. Inthese methods, a subject having an ROH that contains at least 80% of theSNPs in at least one of the three locations identified in SupplementaryTable 2 has an increased risk for manifesting schizophrenia over asubject not having such an ROH.

Preferably, these methods comprise determining whether the subject hasan ROH that contains at least 90% of the SNPs in at least one of thethree locations identified in Supplementary Table 2 as correlated withschizophrenia, wherein a subject having an ROH that contains at least90% of the SNPs in at least one of the three locations identified inSupplementary Table 2 has an increased risk for manifestingschizophrenia over a subject not having such an ROH. Most preferably,the methods comprise determining whether the subject has an ROH thatcontains 100% of the SNPs in at least one of the three locationsidentified in Supplementary Table 2 as correlated with schizophrenia,wherein a subject having an ROH that contains 100% of the SNPs in atleast one of the three locations identified in Supplementary Table 2 hasan increased risk for manifesting schizophrenia over a subject nothaving such an ROH.

These methods can be applied to analysis of human embryos. Thus, theinvention is additionally directed to methods of screening a humanembryo in vitro for the risk of becoming a human manifestingschizophrenia. The methods comprise determining the presence of a firstrun of homozygosity (ROH) in the genome of the embryo, where thepresence of the first ROH indicates the embryo has an increased risk formanifesting schizophrenia over an embryo not having the first ROH. Inthese methods, the first ROH is a series of consecutive singlenucleotide polymorphism (SNP) positions that are homozygous in thesubject from one of roh250, roh321, roh314, roh52, roh15, roh129,roh291, roh55, or roh173 as defined in Table 2.

The individual SNPs in the ROH can be further evaluated for associationwith schizophrenia. The invention is thus further directed to methods ofidentifying a single nucleotide polymorphism (SNP) variant affecting therisk of a human subject for manifesting schizophrenia. The methodscomprise identifying a run of homozygosity (ROH) present more often in afirst population of individuals having schizophrenia than in a secondpopulation of individuals not having schizophrenia, then identifying asingle nucleotide polymorphism (SNP) within the ROH, or within 500 kB ofthe ROH, where a first variant of the SNP is present in the firstpopulation more often than in the second population, where the presenceof the first variant of the SNP in a subject indicates that the subjecthas a greater risk for manifesting schizophrenia than the absence of thefirst variant, Here, an ROH is a series of at least 50 consecutive knownSNP positions that are homozygous in the genome of an individual.

The SNP variant(s) identified from the ROHs can be used to determine therelative risk of schizophrenia. Thus, the invention is directed toadditional methods of determining the relative risk of a human subjectfor manifesting schizophrenia. The methods comprise determining whetherthe subject has a SNP genotype associated with schizophrenia asidentified by the method described immediately above. In these methods,a subject with the SNP genotype has an increased risk for manifestingschizophrenia over a subject with a different genotype.

The SNP identified as above is preferably associated with one of roh250,roh321, roh314, roh52, roh15, roh129, roh291, roh55, or roh173 asdefined in Table 2.

The SNP identified as above can be within an open reading frame.Preferably, the open reading frame is in a gene selected from the groupconsisting of DYNC2H1, PIK3C3, CRHR1, IMP5, MAPT, STH, KIAA1267,LRRC37A, ARL17, LRRC37A2, NSF, WNT3, WNT9B, GOSR2, RPRML, CDC27, CHN1,ATF2, ATP5GS3, DUSP12, ATF6, OLFML2B, NOS1AP, SGCD, MRPL22, GPHN,C14orf54, MPP5, ATP6V1D, EIF2S1, PLEK2, GULP1, DIRC1, COL3A1, COL5A2,WDR75, SLC40A1, NS3TP1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, PMS1, GDF8, andIMPAD1.

The identification of several genes within the schizophrenia-associatedROHs (Table 2) raises the possibility that a compound that affects theproducts of these genes affect schizophrenia. The invention is thusfurther directed to methods of screening for a compound that may affectschizophrenia. The methods comprise determining whether the compoundaffects expression or activity of a gene selected from the groupconsisting of DYNC2H1, CRHR1, IMP5, MAPT, STH, KIAA1267, LRRC37A, ARL17,LRRC37A2, WNT3, WNT9B, GOSR2, RPRML, CDC27, CHN1, ATP5GS3, DUSP12, ATF6,OLFML2B, SGCD, MRPL22, GPHN, C14orf54, MPP5, ATP6V1D, EIF2S1, PLEK2,GULP1, DIRC1, COL3A1, COL5A2, WDR75, SLC40A1, NS3TP1, ASNSD1, ANKAR,OSGEPL1, ORMDL1, PMS1, GDF8, IMPAD1, SNTG1 and SORCS1, Here, a compoundthat affects expression of the gene or activity of the gene product mayaffect schizophrenia. Preferred genes for these methods are MAPT, GPHN,SNTG1 and SORCS1.

In some aspects of these methods, the compound is contacted with aproduct of the gene then the activity of the gene product is measured.Alternatively, the compound is contacted with the product of the gene invitro. In other aspects, the compound is contacted with a cell thatexpresses the product of the gene such that the compound contacts theproduct of the gene. Alternatively, the compound is contacted with acell that is capable of expressing the gene, and expression of the geneis measured and compared to expression of the gene in a cell that is notcontacted with the compound. In other aspects, the compound isadministered to a mammal and activity of a product of the gene ismeasured and compared to activity of the product of the gene in a mammalthat is not administered the compound. In further aspects, the compoundis administered to a mammal and expression of the gene is measured andcompared to expression of the gene in a mammal that is not administeredthe compound.

Preferred embodiments of the invention are described in the followingexamples. Other embodiments within the scope of the claims herein willbe apparent to one skilled in the art from consideration of thespecification or practice of the invention as disclosed herein. It isintended that the specification, together with the examples, beconsidered exemplary only, with the scope and spirit of the inventionbeing indicated by the claims, which follow the examples.

Example 1 Runs of Homozygosity Reveal Highly Penetrant Recessive Loci inSchizophrenia Example Summary

Evolutionarily significant selective sweeps may result in long stretchesof homozygous polymorphisms in individuals from outbred populations.Whole genome homozygosity association (WGHA) methodology was developedto exploit this phenomenon. This methodology was validated byidentifying genetic risk loci for schizophrenia (SCZ). Applying WGHA to178 SCZ cases and 144 healthy controls genotyped at 500,000 markers, itwas found that runs of homozygosity (ROHs), ranging in size from 200 kbto 15 MB, were common in unrelated Caucasians. ROHs were significantlymore common in SCZ, and a set of nine ROHs significantly differentiatedcases from controls. Each of these 9 “risk ROHs” included genes relevantto post-synaptic structure and/or neuronal survival, and four containedor neighbored genes previously associated with SCZ (NOS1AP, ATF2, NSF,and PIK3C3). Results suggest that recessive effects of relatively highpenetrance at CNS-relevant loci may explain a proportion of the geneticliability for SCZ.

Introduction

Structural properties of whole genome association (WGA) datasets,including patterns of linkage disequilibrium (LD), have not yet beenexploited in WGA analyses. Consequently, a novel analytic approach wasdeveloped, termed whole genome homozygosity association (WGHA). WGHAfirst identifies patterned clusters of SNPs demonstrating excesshomozygosity and then employs both genomewide and regionally-specificstatistical tests for association to disease. In the present study, WGHAwas utilized in a case-control dataset of patients with schizophrenia(SCZ, MIM #181500) and healthy volunteers, genotyped at ˜500,000 SNPs,to detect novel susceptibility loci for SCZ.

WGHA (described in detail below) presents an opportunity for rapidlyidentifying susceptibility loci broadly across the genome, yet withresolution sufficient to implicate a circumscribed set of candidategenes. WGHA is designed to be sensitive for detecting loci underselective pressure, and recent data suggests that signatures ofevolutionary selection may be strongly observed in genes regulatingneurodevelopment (Williamson et al., 2007; Evans et al., 2005). Thus,WGHA may be particularly effective for a disorder such as SCZ, which isthought to have a primary pathophysiological basis in abnormalneurodevelopmental processes (Kamiya et al., 2005).

Regions of extended homozygosity across large numbers of consecutiveSNPs form the basis of WGHA analysis. In general, extent of homozygosityis a function of LD within a chromosomal region, which in turn is afunction of recombination rates and population history (McVean et al.,2004; Reich et al., 2002; Coop and Przeworski, 2007). Size and structureof LD blocks vary widely across the genome and across populations (Hindset al., 2005), and regions of extensive long-range LD may be indicativeof selective sweeps of functional significance (Kim and Nielson, 2004).For example, variants of the extended haplotype homozygosity test(Sabeti et al., 2002) have been used to examine identity-by-descentacross unrelated chromosomes in HapMap (International HapMap Consortium,2005) and other population samples, identifying known loci underselection (e.g., LCT in Europeans) (Voight et al., 2006; Wang et al.,2006). A logical consequence of such identity across unrelatedchromosomes is that long stretches of homozygosity may be observed inhealthy individuals from outbred populations lacking any knownconsanguineous parentage (Gibson et al., 2006; Simon-Sanchez et al.,2007). However, the relative commonality of this phenomenon has not beensystematically documented in large datasets at high resolution.Moreover, while homozygosity mapping has successfully identified diseaseloci in pedigrees marked by Mendelian illness (Miyazawa et al., 2007),the ability of such a method to detect susceptibility loci in commondisease has not been examined in a case-control study. Data is presentedhere addressing both normal patterns of homozygosity and use of thesepatterns in WGHA mapping of SCZ.

Subjects and Methods

Participants. As described previously (Lencz et al., 2007), patientswith SCZ spectrum disorders (total n=178, including 158 patients withschizophrenia, 13 patients with schizoaffective disorder, and 7 withschizophreniform disorder) were recruited from the inpatient andoutpatient clinical services of The Zucker Hillside Hospital, a divisionof the North Shore-Long Island Jewish Health System. After providingwritten informed consent, the Structured Clinical Interview for DSM-IVAxis I disorders (SCID, version 2.0) was administered by trained raters.Information obtained from the SCID was supplemented by a review ofmedical records and interviews with family informants when possible; alldiagnostic information was compiled into a narrative case summary andpresented to a consensus diagnostic committee, consisting of a minimumof three senior faculty.

Healthy controls (n=144) were recruited by use of local newspaperadvertisements, flyers, and community Internet resources and underwentinitial telephone screening to assess eligibility criteria. Afterproviding written informed consent, the nonpatient SCID (SCID-NP) wasadministered to subjects who met eligibility criteria, to rule out thepresence of an Axis I psychiatric disorder; a urine toxicology screenfor drug use and an assessment of the subject's family history ofpsychiatric disorders were also performed. Exclusion criteria included(current or past) Axis I psychiatric disorder, psychotropic drugtreatment, substance abuse, a first-degree family member with an Axis Ipsychiatric disorder, or the inability to provide written informedconsent. Patients (65 female/113 male) and controls (63F/81 M) did notsignificantly differ in sex distribution (P>0.05).

All subjects self-identified as Caucasian, non-Hispanic. As describedpreviously (Lencz et al., 2007), population structure was tested byexamination of 210 ancestry informative markers (AIMs). AIMs includedall SNPs on the array that passed initial quality control procedures anddemonstrated a frequency difference of ≧0.5 in comparisons betweenCaucasian individuals and Asians or African-Americans in data madepublicly available by Shriver and colleagues (Shriver et al., 2003)(http://146.186.95.23/biolab/voyage/psa.html). Two tests of structurewere performed, both of which indicated no significant stratification.First, analysis with the STRUCTURE program (Pritchard et al., 2000)confirmed that all subjects were drawn from a single population; second,comparison of cases and controls on allelic frequency across the 210AIMs revealed no differences beyond those expected by chance.

Genotyping. Genomic DNA extracted from whole blood was hybridized to twooligonucleotide microarrays (Kennedy et al., 2003) containing ˜262,000and ˜238,000 SNPs (mean spacing=5.8 kb; mean heterozygosity=27%) as permanufacturer's specifications (Affymetrix, Santa Clara, Calif.; S3).Genotype calls were obtained using the Bayesian Robust Linear Model withMahalanobis distance classifier (BRLMM) algorithm thresholded at 0.5applied to batches of 100 samples. Quality control procedures followedseveral steps (Lencz et al., 2007). First, samples that obtained meancall rates <90% across both chips (or <85% for a single chip) wererejected. Mean call rate of remaining samples (total n=322) was 97%.Twenty-two of these cases were successfully repeated, and concordance ofthe two calls (reliability) for each SNP was evaluated. SNPs with >1discrepancy were excluded from further analyses. Concordance across theremaining 454,699 SNPs exceeded 99.4%. For WGHA, individual SNPs withlow call rates even in valid cases were included, as were SNPs not inHardy-Weinberg equilibrium in the control sample, because SNPs withthese properties may be indicative of structural genomic variation ofinterest (McCarroll et al., 2006). However, 9936 SNPs in the sex-linked(i.e., non-pseudoautosomal) portion of the X chromosome were deleted,yielding 444,763 SNPs available for WGHA analysis. All statisticalanalyses described above were conducted using HelixTree software (GoldenHelix, Inc., Bozeman, Mont.).

WGHA: Definitions and Statistical Analysis. WGHA analysis entailsseveral within-subject and across-subject analytic steps, each performedwith customized python scripting in the HelixTree environment, asfollows. First, SNP data from each chromosome of each subject wereinterrogated for runs of homozygosity (ROHs), which are long series ofconsecutive SNPs that are homozygous (uncalled SNPs are permitted withina run, as these may indicate genomic phenomena of interest). Aconservative threshold of 100 consecutive SNPs was selected to minimizefalse positive identification of ROHs occurring by chance (at theadmitted risk of false negatives). Since mean heterozygosity across allSNPs was observed to be 27%, any given SNP has, on average, a 0.73chance of being called homozygous. Given 444,763 reliable SNPs and 322subjects, a minimum run length of 70 would be required to produce <5%family-wise error rate (i.e., randomly generated ROHs) across allsubjects (0.73⁷⁰*444,763*322=0.04), assuming complete independence ofall SNPs. Due to linkage disequilibrium, SNP calls are not fullyindependent, thereby inflating the likelihood of chance occurrence ofbiologically meaningless ROHs. Genomewide identification of tag SNPswithin windows of 70 markers using the Carlson method (Carlson et al.,2004) as implemented in HelixTree revealed 314,869 separable tag groups,representing a 29.3% reduction of information compared to the totalnumber of original SNPs. Thus, run size of 100 SNPs was selected toapproximate the degrees of freedom of 70 independent SNP calls.

Each subject's SNP data were then converted to binary calls (0 or 1) ateach position indicating whether that SNP is a member of an ROH for thatindividual. Next, at each position, data from all subjects was examinedto determine whether a minimum number of individuals share an ROH callat a given position. Since the purpose of this investigation was theidentification of statistical differences between biologicallymeaningful ROHs in a case-control design, SNPs with <10 ROH calls acrossthe entire sample were eliminated, resulting in 65,422 SNPs with 10 ormore ROH calls, an 85% reduction from the original pool of SNPs. Takingthis strategy a step further, ‘common’ ROHs were identified whichcontained a minimum of 100 consecutive ROH calls across 10 or moresubjects. A total of 339 such ROHs were identified across the genome,ranging in size from 100 to 852 SNPs in length (mean=161, SD=82,median=133, see Supplementary Table 1). A subject whose individual ROHcalls overlapped with a common ROH was called ‘present’ for that commonROH. Thus, each subject could have a total (sum) score for presence ofcommon ROHs ranging from 0 to 339.

Based on these definitions, the statistical plan followed several stepsfor the identification of differences between cases and controls. First,this total score for common ROHs was compared between cases and controlsusing Student's t-test; this constituted a single genomewide test fordifference in ROH frequency, with a set to 0.05. Next, as a plannedpost-hoc examination of any significant genomewide difference,case-control comparisons of frequency of presence for each common ROHwere examined using χ² tests (or Fisher's exact test when expectedvalues <10 were found for any cell); although a would be protected bythe preceding genomewide comparison, the threshold for significance forthis analysis was set to p<0.01 to further reduce the risk of falsepositives. Third, the cumulative effect of these risk-imparting ROHs(i.e., the dose-dependence of the presence of “risk ROHs”) was testedwith logistic regression. Because the predictor variables for theselogistic regression analyses were the ROHs already identified assignificantly differentiating cases and controls, the raw p-values forthese regressions should be considered as strongly anti-conservative.Therefore, empirical p-values were calculated using 100,000 permutationsof the full ROH dataset for each regression analysis.

Finally, as an exploratory analysis to potentially identify smallerregions of difference between cases and controls, χ² tests wereperformed on the 54,600 binarized SNP calls within common ROHs.Analogous to the dual-thresholding procedures commonly used in voxelwisebrain imaging studies (Poline et al., 1997), statistical significancefor these exploratory analyses was defined as 50 or more consecutiveSNPs significantly differing between cases and controls at the p<0.01level.

A summary version of the WGHA algorithm, as described above, ispresented in pseudo-code form below. Assuming each subject isrepresented by a spreadsheet row and each QC-validated SNP on themicroarray is represented by a spreadsheet column:

-   -   1) For each individual, scan across raw SNP data for runs of        consecutive homozygous (or missing) calls >100 SNPs in length.    -   2) For each individual, recode each SNP call to a ‘0’ or ‘1’        indicating whether it is a member of an ROH for that individual.    -   3) Across subjects, scan down columns and delete all columns        that contain fewer than ten 1's.    -   4) Construct a list of common ROHs by identifying, across all        subjects, runs of ≧100 SNPs in length in which 10 or more        subjects have consecutive 1's.    -   5) For each subject, mark each common ROH as ‘present’ if that        subject contains any 1's within the boundaries of that ROH.    -   6) Conduct primary case-control analyses on scores derived from        step 5 above. Genomewide analysis is conducted on the sum score        across all ROHs. Given a significant genomewide case-control        difference, individual ROHs can be examined for frequency        differences to identify the source of this overall difference.    -   7) Conduct exploratory case-control analyses on binarized SNP        scores derived from step 2 above. Significant case-control        differences can be identified utilizing a two-step threshold        (analogous to “height” and “extent” in voxelwise brain imaging        studies): first, identify all SNPs at which case-control        frequency differences are significant (p<0.01). Then, identify        any runs of significant difference extending 50 or more SNPs in        length. In the present study, this exploratory analysis resulted        in the subregions listed in Supplementary Table 2.

Results

As described above, the critical step of WGHA analysis is theidentification of “common” runs of homozygosity” (ROHs) defined as thoseROHs in which 10 or more subjects share ≧100 identical homozygous calls.Each common ROH was then scored “present” or “absent” for each subject.A total of 339 common ROHs were thus identified (Supplementary Table 1),encompassing approximately 12-13% of the genome as measured both bynumber of included SNPs and total chromosomal length. The six longestROHs, ranging from 6 MB to 15.6 MB, encompass the centromeres ofchromosomes 3, 5, 8, 11, 16, and 19. In part, this is a function of longregions with no SNPs ascertained; nevertheless, in each case, thesecentromeric gene deserts are flanked by homozygous regions containinghundreds of SNPs, possibly reflecting meiotic drive (Williamson et al.,2007). The greatest number of consecutive SNPs (852) is found in roh172,spanning the centromere of Chromosome 8; this region, which contains thegene encoding syntrophin gamma 1 (SNTG1), has been previouslyhighlighted in several genomewide studies of selective sweeps(Williamson et al., 2007; International HapMap Consortium, 2005; Voightet al., 2006; Wang et al., 2006), thereby providing a positive controlfor our method.

There are 9 ROHs that were very common (>25% frequency) in healthycontrols. As displayed in Table 1, publicly available data indicatesthat these regions are not marked by excessive copy number variation orsegmental duplication. Moreover, these ROHs do not appear to haveabnormally low recombination rates; the Phase II HapMap shows an averageof about 5 recombination hotspots/MB across these 9 regions(International HapMap Consortium, 2005). On the other hand, examinationof Haplotter data (Voight et al., 2006)(http://hg-wen.uchicago.edu/selection/haplotter.htm) indicates highscores for each of these regions on one or more measures of positiveselection in Caucasian samples (iHS, Tajima's D, and/or Fst). Severalgene categories previously identified in studies of selective pressure(Williamson et al., 2007; International HapMap Consortium, 2005; Voightet al., 2006; Wang et al., 2006) are evident in these regions, includinggenes involved in the immune system (on chromosomes 6p, 12q and 5q),olfactory receptors (6p and 11p), members of the dystrophin proteincomplex (SNTG1 and DGKZ), and many other CNS-expressed genes (e.g.,GPI-IN, UNC5D, ATXN2).

TABLE 1 List of 9 ROHs with frequency ≧25% in the healthy cohort (n =144). Chromosomal coordinates listed from NCBI Build 35. Columns I, J,and K represent maximal values for alternate metrics of positiveselection, derived from Haplotter (ref. 15, http://hg-wen.uchicago.edu/selection/haplotter.htm). Number of deletions and duplications containedwithin each region derived from ref. 30(http://projects.tcag.ca/variation). Percentage of each ROH containingsegmental duplication and number of recombination hotspots estimatedfrom HapMap version 21a (ref. 14, http://hapmap.org). Length # N % iHSTajimaD Fst # Deletions/ % # ROH Chr Start (B35) End (B35) (bp) SNPsControl Control max max max # Duplications Seg_Dup HotSpots roh172 842588087 53273605 10685518 852 77 53.5 3.90 2.00 0.90 0/6 0.00 32.00roh134 6 26216147 29800284 3584137 489 52 36.1 2.40 1.50 0.52 0/3 0.1013.00 roh89 4 32428277 34888919 2460642 252 52 36.1 3.50 2.40 0.62 9/20.05 17.00 roh241 11 46212732 49874378 3661646 323 48 33.3 2.30 1.750.70 11/1  0.35 3.00 roh291 14 65475183 67065410 1590227 197 47 32.62.50 2.75 0.99 0/0 0.00 9.00 roh171 8 33590815 36749387 3158572 443 4128.5 0.60 2.80 0.42 0/0 0.00 19.00 roh238 11 37492528 40090659 2598131386 39 27.1 1.10 5.10 0.45 0/0 0.00 25.00 roh275 12 109752647 1117334451980798 205 37 25.7 1.10 1.80 0.22 0/0 0.00 8.00 roh125 5 129481382132022568 2541186 286 36 25.0 1.20 1.25 0.65 1/1 0.00 12.00

The total number of common ROHs marked “present” was summed for eachsubject to permit genomewide comparison across diagnostic groups, priorto group comparisons of frequency of individual ROHs. Out of a totalpossible sum score of 339, patients with schizophrenia demonstrated asignificantly greater number of common ROHs scored ‘present’ (mean=31.7,SD=12.3) relative to healthy volunteers (mean=28.0, SD=12.8; t₃₂₀=2.62,P=0.009). Nine individual ROHs significantly <0.01) differed infrequency between cases and controls (Table 2); each was more common inSCZ cases.

TABLE 2 List of 9 risk ROHs significantly over-represented in SCZ cases(p < .01). Genes previously associated with SCZ listed in bold. N % N %ROH Chr Start (B35) End (B35) Length # SNPs Cases Cases Control ControlX² P Genes roh250 11 102488778 102947117 458339 103 14 7.9 0 0.0 Fisher0.0004 DYNC2H1 roh321 18 37022928 37619977 597049 119 15 8.4 1 0.7Fisher 0.0012 (PIK3C3) roh314 17 41169023 42622984 1453961 211 40 22.514 9.7 9.271 0.0023 CRHR1; IMP5; MAPT; STH; KIAA1267; LRRC37A; ARL17;LRRC37A2; NSF; WNT3; WNT9B; GOSR2; RPRML; CDC27 roh52 2 175671012176445047 774035 115 17 9.6 2 1.4 Fisher 0.0032 CHN1; ATF2; ATP5GS3roh15 1 158440777 159015569 574792 173 20 11.2 4 2.8 8.256 0.0041DUSP12; ATF6; OLFML2B; NOS1AP roh129 5 154592379 155033077 440698 116 137.3 1 0.7 Fisher 0.0042 (SGCD, MRPL22) roh291 14 65475183 670654101590227 197 86 48.3 47 32.6 8.068 0.0045 GPHN; C14orf54; MPP5; ATP6V1D;EIF2S1; PLEK2 roh55 2 188489676 190772106 2282430 274 31 17.4 10 6.97.855 0.0051 GULP1; DIRC1; COL3A1; COL5A2; WDR75; SLC40A1; NS3TP1;ASNSD1; ANKAR; OSGEPL1; ORMDL1; PMS1; GDF8 roh173 8 57989122 58616467627345 120 20 11.2 5 3.5 6.7 0.0096 IMPAD1

Several features of these 9 “risk ROHs” are notable. First, presence ofthe risk ROHs is not common in healthy subjects, and presence of severalis exceedingly rare in healthy subjects (Table 3). Greater than half(54.9%) of healthy controls, but only 19.1% of SCZ subjects, did nothave any risk ROHs present in their WGHA data (χ²=44.7, df=1,P=2.3*10⁻¹¹; permuted P=0.0022; Odds Ratio=5.15, 95% CI=3.13-8.46).Moreover, as the number of risk ROHs increases, risk of illnessincreases dramatically. Using logistic regression, total number of riskROHs significantly predicted group status (χ²=62.6, df=1, P=2.51*10⁻¹⁵;permuted P=0.00095; with each additional risk ROH imparting an oddsratio of 2.83 (95% CI=2.10-3.81, see also Table 3).

TABLE 3 Odds of SCZ as a function of number of risk ROHs present in agiven individual. Odds ratios computed using sum = 0 as referencecategory. For purposes of calculation, individuals with ≧3 risk ROHswere grouped together. #Risk N ROHs (Sum) Cases % Cases N Control %Control OR* 95% CI 0 34 19.1 79 54.9% 1 70 39.3 49 34.0% 3.3 1.9-5.7  243 24.2 13 9.0% 5.4 3.7-16.1 3 25 14.0 3 2.1% 24**  6.9-83.9 4 5 2.8 00.0% 5 1 0.6 0 0.0% *OR compared to Sum = 0. **Sum ≧3 compared to Sum =0.

Six of the nine risk ROHs listed in Table 2 are extremely rare inhealthy controls. One ROH (roh250), containing the gene encoding thedynein cytoplasmic 2, heavy chain 1 protein (DYNC2H1 on chromosome 11q), was exclusively observed in SCZ; in other words, this geneticvariant demonstrated 100% penetrance for illness. On the other hand, onevery common ROH in healthy subjects (roh291) also conferred risk for SCZ(χ²=8.1, df=1, P=0.0045). This ROH is centered on the very large (˜675kb) gene GPHN, which codes for gephyrin, a protein scaffold that servesto anchor GABA receptors in the postsynaptic membrane.

As with GPHN, the genes implicated in all but one of these regions(roh55) are amenable to neurodevelopmental interpretations consistentwith known or hypothesized SCZ pathophysiological mechanisms (Kamiya etal., 2005). Specifically, roh15 on chromosome 1q contains NOS1AP(formerly CAPON), which has been related to schizophrenia in bothgenetic linkage and association studies, as well as in post-mortem geneexpression studies (Brzustowicz et al., 2004; Zeng et al., 2005; Xu etal., 2005). This protein competes with PSD95 for binding to neuronalnitric oxide synthase (nNOS), thereby disrupting neuronal NMDA receptortransmission at the post-synaptic density. Similarly, roh52 containsATF2, a downstream target of the mitogen-activated proteinkinase/extracellular signal-regulated kinase signaling pathway triggeredby nNOS; protein levels of activating transcription factor 2 have beenreported to be elevated in postmortem SCZ brain tissue (Kyosseva et al.,2000). Further, roh314 contains NSF (encoding a critical presynapticprotein, N-ethylmaleimide sensitive fusion), which regulatesdissociation of the SNARE complex and binds to the GluR2 subunit of AMPAglutamate receptors. Abnormalities in this gene have been also linkedwith schizophrenia in both gene expression and genetic associationstudies (Mimics et al., 2000; Allen et al., 2007). In addition to NSF,roh314 (at chromosome 17q21) contains MAPT (microtubule-associatedprotein tau). MAPT has been previously reported to contain a commoninversion under selective pressure, resulting in a distinctivehaplotypic genealogy that has been associated with multiple neurologicaldisorders, including Alzheimer's disease, fronto-temporal dementia, andprogressive supranuclear palsy (Hardy et al., 2006).

Two ROHs which were significantly over-represented in patients with SCZcontained no known genes (roh321 on chromosome 18q and roh129 on 5q).While both regions include one or more ESTs and may harbor as-yetunknown regulatory elements, it is also possible that extensive allelichitchhiking may result in effects on genes immediately neighboring theseregions (McVean et al., 2004). Consequently, the first gene locatedwithin 500 kb in either direction of these ROHs is listed in parenthesesin Table 2. PIK3C3 (adjacent to roh129) encodesphosphoinositide-3-kinase, class 3, which is highly expressed throughoutthe brain. A promoter region variant in this gene has been associatedwith SCZ in three studies to date (Allen et al., 2007). Moreover, thePI3K/AKT signaling cascade modulates activation of ErbB4 receptors inoligodendrocytes, which are activated by neuregulin, widely considered aSCZ risk gene (Allen et al., 2007; Law et al., 2007).

Finally, exploratory analyses examining binarized individual SNP datarevealed subregions of two additional ROHs which were significantlyover-represented in SCZ cases relative to controls (Supplementary Table2). Segments of the very large ROH on chromosome 8 (roh172),demonstrated a strong differentiation between cases and controls(maximal χ²=12.9, df=1, P=3.28*10⁴) occurring directly in the codingregion of SNTG1 (FIG. 1). SNTG1 is expressed exclusively in neurons,including hippocampal pyramidal cells, cerebellar Purkinje cells, andmultiple cortical regions, where it binds to dystrophin, thedystrobrevins, and diacylglycerol kinase, zeta (DGKZ) in thepost-synaptic density. SORCS1, which is widespread throughout the brainand has been recently characterized as a gamma-secretase substrate, wasalso identified as a significant subregion of an ROH on chromosome 10q.

Discussion

Taken together, these data suggest the utility of WGHA in identifyingdisease-relevant genomic regions of interest, and support severalhypotheses concerning the genetic architecture of SCZ. Utilizing dense,whole-genome microarray SNP data, we observed that runs of homozygosityranging in size from 200 kb to more than 15 MB were common even inhealthy individuals from an outbred population (U.S. Caucasians residingin New York City/Long Island). These homozygous regions are both toocommon and too small to suggest recent consanguineity. Rather,convergence with prior reports suggests that ROHs mark regions underselective pressure. The most common ROHs in the present study (Table 1)have generally been implicated in prior studies using varying coalescentmodels and statistical assumptions (Williamson et al., 2007;International HapMap Consortium, 2005; Voight et al., 2006; Wang et all,2006). At the same time, genes recognized by other methods as understrong selective pressure in Caucasians, such as SNTG1 (included inroh172), ALDH2 (roh275), LCT (roh45), and SLC24A5 (roh296), aresuccessfully captured amongst the common ROHs listed in SupplementaryTable 1.

Because the SNP selection of the current generation of whole-genomemicroarrays is still limited and does not permit uniform coverage acrossthe genome, the likelihood of SNP ascertainment bias limits formalstatistical testing of the evidence for selection (Clark et al., 2005).However, relative frequency of these ROHs in an unselected, healthyCaucasian population provides a metric that is significantly correlatedwith other measures of selection (Voight et al., 2006). Across regions,ROH frequency in controls was significantly correlated with maximal iHS(r=0.33, P=3.4*10⁻¹⁰) and Tajima's D (r=0.30, P=2.8*10⁻⁸); thesecorrelations are comparable to the intercorrelation of maximal iHS and Dfor the same regions (r=0.30, P=1.3*10⁻⁸). Moreover, ROH frequency is areadily available measure for statistical comparisons in a case-controldesign. Thus, current and future generations of commercially availablegenotyping microarrays can provide evolutionarily-meaningful data at thegenomic level.

We also observed that ROHs were over-represented in SCZ cases at agenomewide level, and that presence of nine specific ROHs was associatedwith illness susceptibility both individually and cumulatively.Intriguingly, genes found in these regions tended to converge upon alimited number of CNS-relevant pathways. Four of these regionsimplicated genes related to post-synaptic (largely glutamatergic)receptor complexes previously implicated in SCZ pathophysiology. Thesegenes include NOS1AP and NSF, each of which has been previouslyassociated with schizophrenia, as well as GPHN and SGCD, which have notbeen previously examined in SCZ association studies. A fifth regionspanning the coding region of SNTG1 was associated with SCZ inexploratory analyses; syntrophin abnormalities in SCZ are consistentwith the accumulating evidence associating DTNBP1 haplotypic variationwith SCZ susceptibility (Allen et al., 2007; Funke et al., 2004).

Five risk ROHs (including one identified in the exploratory analysis)contain or neighbor genes related to neuronal proliferation andsurvival, either via the phosphatidylinositol signaling pathway (IMPAD1and PIK3C3), activating transcription factors (ATF2 and ATF6), orthrough binding with growth factors (SORCS1). Additionally, it isnotable that the risk ROH with the strongest association toschizophrenia contained only one gene, encoding a dynein subunit.Although DYNC2H1 is not as well characterized as other cytoplasmicdynein subunits (which bind with the well-studied schizophrenia riskgene DISCI [Kamiya et al., 2005; Allen et al., 2007; Hodgkinson et al.,2004]), the implication of microtubule dysgenesis is consistent withcurrent pathophysiological hypotheses in SCZ⁷, and converges with theimplication of MAPT in an additional risk ROH.

It should be noted that results for the MAPT region may be influenced bythe frequent presence of copy number variation at chromosome 17q21(Redon et al., 2006); however, it is unlikely that results of thepresent study are primarily reflective of copy number variation, forfour reasons. First, HapMap data suggests that duplications in thisregion are far more common than deletions (Redon et al., 2006), whereasdeletions are more likely to create a spurious pattern of homozygouscalls (McCarroll et al., 2006). Second, deletions in this region havebeen associated with mental retardation (Sharp et al., 2006), which isnot observed in our study. Third, chromosomal locations containinghighly common ROHs (Table 1) are not generally marked by frequent copynumber variation in publicly available databases (Redon et al., 2006).Fourth, inspection of raw intensity plots from microarrays analyzed forthe present study are not consistent with frequent, large regions ofcopy number variation in the neighborhood of common ROHs (data notshown). Further research is needed to carefully examine the role of copynumber variation in SCZ.

Finally, if ROHs provide an index of genomic regions undergoing positiveselection, it is perhaps counterintuitive that ROHs would be morecommonly observed in patients with schizophrenia. However, results areconsistent with a model of rare, deleterious recessive effectsassociated with an allele or haplotype with positive co-dominantproperties (Voight et al., 2006). These balancing effects may either bethe result of the same allele, as in HBB and malaria, or from distalalleles that have hitchhiked near a region undergoing selection. It hasbeen suggested that an example of the latter is hereditaryhemochromatosis, a relatively common recessive disorder involving amutation in HFE. While some evidence suggests that the FIFE mutationitself is subject to balancing selection, a recent genomewide scan forevolutionary signal indicated that positive selection was more likely tobe acting on the adjacent large histone cluster at chromosome 6p22(Williamson et al., 2007); this histone cluster (but not HFE) was alsothe site of a relatively common ROH (roh134) in the present study. WhileWGHA currently lacks the spatial resolution to identify the causativeallele(s), regions reported in the present study provide fairly narrowwindows containing highly plausible candidates for furtherinvestigation. They also suggest that recessive effects of relativelyhigh penetrance at multiple loci may explain a proportion of the geneticliability for SCZ.

SUPPLEMENTARY TABLE 1 List of all 339 common ROHs. Start and stoppositions are listed as a function of chromosomal position (both Build35 and Build 34 coordinates are presented), SNP Affymetrix ID's, and SNPrs numbers. ROH Chr Start_Cyto Stop_Cyto Start_pos End_pos Length #SNPsStart_Affy End_Affy Start_rs roh2 1 p35.2 p35.2 31180097 31783886 603789107 A-2296736 A-2000348 rs7537241 roh3 1 p34.3 p34.3 34972868 365738531600985 118 A-4256194 A-4219724 rs6655940 roh4 1 p34.1 p34.1 4511313146347229 1234098 115 A-1913736 A-2030685 rs11556200 roh5 1 p33 p32.348801467 50466576 1665109 182 A-4241953 A-2261210 rs11807595 roh6 1p32.3 p32.2 55603820 56532672 928852 245 A-2041390 A-2026309 rs11206580roh7 1 p31.1 p31.1 72245948 73882032 1636084 209 A-1898528 A-2277303rs2630380 roh8 1 p31.1 p31.1 75613158 76201800 588642 117 A-2295414A-1898797 rs17096877 roh9 1 p31.1 p31.1 80022979 80639208 616229 115A-1849732 A-2267047 rs17103827 roh10 1 p22.2 p22.2 88567123 89184874617751 103 A-1938599 A-4285123 rs443499 roh11 1 p21.3 p21.3 9630720097160204 853004 131 A-2071697 A-1854765 rs1222069 roh12 1 p21.2 p21.299997212 100910847 913635 123 A-2283986 A-1849514 rs11166349 roh13 1p21.1 p21.1 102463733 103469102 1005369 133 A-4244090 A-1907564rs1578575 roh14 1 q21.3 q21.3 149214350 150010691 796341 199 A-1855975A-2160307 rs6587671 roh15 1 q23.3 q23.3 158440777 159015569 574792 173A-1901847 A-1969201 rs1503814 roh16 1 q23.3 q23.3 160689111 161146399457288 103 A-2190181 A-1823445 rs16823642 roh17 1 q24.1 q24.1 163223096163719936 496840 106 A-2199679 A-2181943 rs1021499 roh18 1 q24.2 q24.2166355252 166835037 479785 125 A-2203047 A-4263351 rs7535059 roh19 1q25.1 q25.1 170121297 171823807 1702510 168 A-2000482 A-4251147rs4294450 roh20 1 q25.1 q25.2 172525946 173746872 1220926 187 A-1790335A-1826369 rs476146 roh21 1 q25.3 q25.3 179311585 180284983 973398 156A-2178976 A-1859825 rs609990 roh22 1 q25.3 q31.1 182247118 182909895662777 114 A-1975823 A-4299638 rs1321996 roh23 1 q31.1 q31.1 185525129186689757 1164628 131 A-2000558 A-1908476 rs7519600 roh24 1 q31.1 q31.2186802518 187568490 765972 116 A-1977181 A-1870345 rs16832009 roh25 1q31.3 q31.3 190656365 191449984 793619 116 A-1914869 A-2064189rs12353935 roh26 1 q41 q41 216196369 216833320 636951 113 A-4226649A-2219189 rs17006203 roh27 1 q42.12 q42.12 220962951 221800318 837367130 A-2036007 A-4265758 rs10753470 roh28 1 q43 q43 232999736 233305452305716 106 A-2076452 A-2235968 rs16833729 roh29 2 p24.2 p24.2 1717020117921554 751353 133 A-1962289 A-2024711 rs7592574 roh30 2 p24.1 p24.121376150 22452456 1076306 154 A-1917234 A-2074117 rs312042 roh31 2 p22.1p22.1 38866070 39865134 999064 145 A-2204016 A-1962860 rs11124646 roh322 p22.1 p22.1 39979675 40403864 424189 130 A-2136038 A-1941421 rs3953508roh33 2 p22.1 p21 41472377 41814193 341816 104 A-1870597 A-4270895rs6750424 roh34 2 p16.3 p16.2 52794897 53269856 474959 123 A-1903359A-4251321 rs1454402 roh35 2 p16.1 p16.1 57678029 58404092 726063 115A-2043789 A-4236460 rs4671309 roh36 2 p12 p12 81577055 82119607 542552108 A-2161985 A-1956032 rs17020238 roh37 2 p12 p11.2 82180277 849779032797626 414 A-2234661 A-2106559 rs1521690 roh38 2 p11.2 p11.2 8600685986786032 779173 152 A-4304347 A-2006529 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A-1969847 A-2017806 rs2248708 roh338 22q12.1 q12.2 26554620 28931481 2376861 297 A-4302541 A-2240075 rs16985600roh339 22 q12.2 q12.3 29851365 30990000 1138635 157 A-1819087 A-2217887rs5753469 roh340 22 q13.1 q13.2 39038116 41012088 1973972 180 A-4290846A-2194547 rs17001819 ROH End_rs N_Cases %_Cases N_Cntl % Cntl Chi-sq PiHS_max TajimaD_max Fst_max roh2 rs4949455 10 5.6 4 2.8 f 0.276 1.000.10 0.45 roh3 rs4652914 15 8.4 12 8.3 0.001 0.976 3.70 3.70 0.55 roh4rs3845301 12 6.7 10 6.9 0.005 0.943 0.60 0.70 0.15 roh5 rs2938100 2011.2 23 16.0 1.543 0.214 0.80 1.70 0.68 roh6 rs10493208 29 16.3 13 9.03.704 0.054 2.20 1.50 0.30 roh7 rs1909067 23 12.9 27 18.8 2.062 0.1511.20 1.00 0.45 roh8 rs11162069 6 3.4 14 9.7 f 0.021 0.00 0.70 0.20 roh9rs11163019 7 3.9 7 4.9 f 0.786 1.00 0.70 0.30 roh10 rs12085660 7 3.9 85.6 f 0.598 1.50 1.60 0.12 roh11 rs290828 12 6.7 7 4.9 f 0.635 1.70 1.200.09 roh12 rs3181089 11 6.2 5 3.5 f 0.311 1.50 1.40 0.80 roh13rs10493999 13 7.3 9 6.3 f 0.825 1.40 2.20 0.35 roh14 rs16835083 21 11.811 7.6 1.538 0.215 0.50 1.10 0.30 roh15 rs2819327 20 11.2 4 2.8 8.2560.004 0.50 1.40 0.50 roh16 rs1387353 11 6.2 1 0.7 f 0.014 0.00 0.50 0.20roh17 rs6673720 8 4.5 6 4.2 f 1.000 0.25 1.00 0.45 roh18 rs471569 16 9.04 2.8 f 0.034 0.50 1.00 0.20 roh19 rs16847820 22 12.4 18 12.5 0.0010.970 1.50 1.00 0.58 roh20 rs7416836 14 7.9 12 8.3 0.024 0.878 1.50 1.700.35 roh21 rs16861188 10 5.6 9 6.3 f 0.817 1.60 2.00 0.48 roh22rs13375677 11 6.2 8 5.6 f 1.000 1.50 0.50 0.20 roh23 rs1730733 16 9.0 96.3 0.834 0.361 1.60 1.60 0.20 roh24 rs1370881 13 7.3 5 3.5 f 0.152 0.600.70 0.35 roh25 rs10921643 12 6.7 9 6.3 f 1.000 1.70 0.50 0.12 roh26rs2808019 15 8.4 3 2.1 f 0.014 2.00 1.50 0.48 roh27 rs10495234 15 8.4 64.2 f 0.173 0.25 1.00 0.35 roh28 rs3820573 16 9.0 4 2.8 f 0.034 0.600.25 0.15 roh29 rs4832500 12 6.7 6 4.2 f 0.343 0.25 1.40 0.10 roh30rs4302239 16 9.0 8 5.6 1.36 0.243 0.00 3.70 0.25 roh31 rs7603886 14 7.911 7.6 0.006 0.940 1.20 2.20 0.65 roh32 rs410259 11 6.2 8 5.6 f 1.0000.50 1.40 0.55 roh33 rs6738287 8 4.5 8 5.6 f 0.798 0.25 0.20 0.25 roh34rs13414722 10 5.6 7 4.9 f 0.808 0.80 0.40 0.25 roh35 rs9789714 4 2.2 117.6 f 0.031 0.75 1.00 0.42 roh36 rs7606191 9 5.1 5 3.5 f 0.589 2.70 0.500.00 roh37 rs736711 45 25.3 29 20.1 1.189 0.276 1.50 2.25 0.20 roh38rs6547701 17 9.6 10 6.9 0.704 0.402 0.50 1.10 0.30 roh39 rs6708290 137.3 10 6.9 0.015 0.901 0.55 0.50 0.15 roh40 rs17048379 9 5.1 11 7.6 f0.362 1.20 1.00 2.10 roh41 rs6728856 22 12.4 12 8.3 1.366 0.242 1.251.20 0.57 roh42 rs17821815 27 15.2 31 21.5 2.18 0.140 1.20 1.50 0.60roh43 rs13385327 8 4.5 7 4.9 f 1.000 0.75 0.70 0.10 roh44 rs6431110 1810.1 12 8.3 0.298 0.585 0.75 0.25 0.50 roh45 rs1432231 24 13.5 15 10.40.703 0.402 4.50 2.20 0.38 roh46 rs1370504 22 12.4 19 13.2 0.05 0.8232.25 1.50 0.42 roh47 rs16842296 8 4.5 7 4.9 f 1.000 1.50 2.50 0.72 roh48rs2528632 8 4.5 9 6.3 f 0.618 2.25 1.40 0.60 roh49 rs7594813 13 7.3 149.7 0.606 0.436 1.50 1.75 0.45 roh50 rs11900934 9 5.1 8 5.6 f 1.000 0.253.80 0.58 roh51 rs16853735 8 4.5 8 5.6 f 0.798 2.10 1.70 0.40 roh52rs16863378 17 9.6 2 1.4 f 0.002 2.60 1.50 0.28 roh53 rs4638831 26 14.629 20.1 1.72 0.190 2.25 1.25 0.40 roh54 rs10203398 26 14.6 12 8.3 3.010.083 1.20 1.25 0.55 roh55 rs785244 31 17.4 10 6.9 7.855 0.005 2.20 1.500.30 roh56 rs9283513 51 28.7 35 24.3 0.768 0.381 2.50 2.00 0.45 roh57rs10211241 15 8.4 13 9.0 0.036 0.849 2.40 0.70 0.70 roh58 rs2887881 105.6 7 4.9 f 0.808 0.75 2.00 0.42 roh59 rs2373146 9 5.1 8 5.6 f 1.0001.20 1.00 0.52 roh60 rs7596956 9 5.1 6 4.2 f 0.795 1.20 1.00 0.52 roh61rs6734283 6 3.4 11 7.6 f 0.131 0.60 2.00 2.20 roh62 rs17039757 11 6.2 64.2 f 0.464 1.00 1.10 0.25 roh63 rs10865897 15 8.4 7 4.9 f 0.268 1.002.80 0.30 roh64 rs9852262 13 7.3 9 6.3 f 0.825 0.25 1.40 0.40 roh65rs17075993 19 10.7 9 6.3 1.962 0.161 0.00 1.20 0.30 roh66 rs6441970 126.7 5 3.5 f 0.219 0.25 0.50 0.30 roh67 rs876597 14 7.9 15 10.4 0.6320.426 1.25 0.75 0.40 roh68 rs1560332 32 18.0 29 20.1 0.242 0.623 1.001.75 0.28 roh69 rs978979 8 4.5 5 3.5 f 0.779 1.20 1.00 0.10 roh70rs17047115 5 2.8 9 6.3 f 0.171 0.80 1.00 0.10 roh71 rs6777604 12 6.7 106.9 f 1.000 1.70 0.70 0.00 roh72 rs17028592 9 5.1 5 3.5 f 0.589 1.751.20 0.20 roh73 rs6548732 19 10.7 13 9.0 0.241 0.623 0.70 1.50 0.42roh74 rs2122355 13 7.3 9 6.3 f 0.825 0.50 1.00 0.10 roh75 rs9857944 137.3 6 4.2 f 0.342 0.25 1.00 0.22 roh76 rs4362744 14 7.9 11 7.6 0.0060.940 0.25 0.75 0.85 roh77 rs1009521 36 20.2 28 19.4 0.03 0.862 1.252.70 0.57 roh78 rs17315194 11 6.2 13 9.0 0.936 0.333 1.40 1.20 0.60roh79 rs17202754 20 11.2 16 11.1 0.001 0.972 1.10 2.40 0.80 roh80rs1518337 10 5.6 9 6.3 f 0.817 2.10 1.40 0.58 roh81 rs16835267 21 11.811 7.6 1.538 0.215 2.80 2.30 0.82 roh82 rs6763412 12 6.7 5 3.5 f 0.2191.00 0.20 0.15 roh83 rs1873521 12 6.7 8 5.6 f 0.817 1.10 0.70 0.00 roh84rs4355238 15 8.4 3 2.1 f 0.014 2.00 0.70 0.35 roh85 rs6782299 11 6.2 149.7 1.395 0.238 1.30 1.40 0.52 roh86 rs6823189 8 4.5 4 2.8 f 0.558 1.602.00 0.50 roh87 rs6812714 22 12.4 21 14.6 0.34 0.560 1.60 1.40 0.30roh88 rs 12502866 5 2.8 7 4.9 f 0.384 1.25 1.20 0.40 roh89 rs7654452 6436.0 52 36.1 0.001 0.977 3.50 2.40 0.62 roh90 rs12502592 7 3.9 7 4.9 f0.786 0.50 1.75 0.30 roh91 rs10805123 12 6.7 8 5.6 f 0.817 0.75 2.000.60 roh92 rs4865408 12 6.7 7 4.9 f 0.635 0.25 1.20 0.97 roh93 rs212423714 7.9 11 7.6 0.006 0.940 3.00 1.80 0.50 roh94 rs1376416 13 7.3 5 3.5 f0.152 0.75 1.20 0.38 roh95 rs16846893 11 6.2 5 3.5 f 0.311 1.80 2.400.65 roh96 rs579866 17 9.6 5 3.5 f 0.044 0.60 1.50 0.50 roh97 rs160415326 14.6 22 15.3 0.028 0.867 0.00 0.70 0.18 roh98 rs13150370 12 6.7 128.3 0.292 0.589 1.00 2.75 0.70 roh99 ? 12 6.7 12 8.3 0.292 0.589 2.751.60 0.58 roh100 rs10857061 12 6.7 6 4.2 f 0.343 2.00 1.50 0.50 roh101rs6534156 16 9.0 6 4.2 f 0.119 0.25 0.60 0.00 roh102 rs10493148 15 8.416 11.1 0.659 0.417 0.70 0.80 0.30 roh103 rs1022006 11 6.2 2 1.4 f 0.0430.00 0.50 0.55 roh104 rs12502464 26 14.6 20 13.9 0.033 0.855 1.50 1.750.60 roh105 rs6537474 13 7.3 13 9.0 0.319 0.572 2.25 1.80 0.22 roh106rs7669465 8 4.5 8 5.6 f 0.798 1.50 3.00 0.60 roh107 rs9994520 8 4.5 74.9 f 1.000 0.60 0.70 0.40 roh108 rs4690909 11 6.2 6 4.2 f 0.464 0.701.50 0.50 roh109 rs1717072 13 7.3 6 4.2 f 0.342 0.60 0.60 0.25 roh110rs17057275 14 7.9 13 9.0 0.14 0.708 1.20 1.25 0.60 roh111 rs10020676 95.1 5 3.5 f 0.589 0.75 0.80 0.38 roh112 rs4701970 10 5.6 7 4.9 f 0.8080.60 1.00 0.35 roh113 rs12108871 13 7.3 10 6.9 0.015 0.901 1.75 1.500.35 roh114 rs351651 11 6.2 10 6.9 f 0.823 0.70 1.20 0.25 roh115rs6882786 22 12.4 16 11.1 0.119 0.730 1.10 1.40 0.25 roh116 rs27964 1910.7 18 12.5 0.261 0.609 1.10 2.10 0.10 roh117 rs6860698 12 6.7 12 8.30.292 0.589 2.30 1.80 0.25 roh118 rs895382 22 12.4 19 13.2 0.05 0.8231.50 0.75 0.30 roh119 rs11960372 6 3.4 10 6.9 f 0.197 1.20 1.20 0.88roh120 rs665369 7 3.9 9 6.3 f 0.441 1.40 2.25 0.45 roh121 rs34798 2011.2 7 4.9 4.211 0.040 0.60 1.50 0.20 roh122 rs10054378 13 7.3 11 7.60.013 0.909 2.80 2.50 0.90 roh123 rs2035414 37 20.8 17 11.8 4.6 0.0321.60 1.20 0.28 roh124 rs26604 14 7.9 13 9.0 0.14 0.708 0.80 0.80 0.70roh125 rs2069744 46 25.8 36 25.0 0.03 0.863 1.20 1.25 0.65 roh126rs11737955 11 6.2 6 4.2 f 0.464 0.50 0.30 0.25 roh127 rs1438733 14 7.921 14.6 3.708 0.054 2.00 2.25 0.65 roh128 rs2277051 14 7.9 5 3.5 f 0.1520.00 1.25 0.55 roh129 rs6580176 13 7.3 1 0.7 f 0.004 1.20 0.60 0.25roh130 rs7700944 10 5.6 7 4.9 f 0.808 0.25 1.60 0.10 roh131 rs4921399 84.5 3 2.1 f 0.357 0.75 0.80 0.15 roh132 rs4246080 16 9.0 5 3.5 f 0.0670.40 0.75 0.12 roh133 rs10214554 13 7.3 12 8.3 0.118 0.731 1.20 0.800.12 roh134 rs1632953 51 28.7 52 36.1 2.036 0.154 2.40 1.50 0.52 roh135? 11 6.2 10 6.9 f 0.823 2.00 0.70 0.00 roh136 rs2067997 17 9.6 11 7.60.366 0.545 3.00 1.70 0.62 roh137 rs2677101 15 8.4 10 6.9 0.244 0.6210.00 0.75 0.08 roh138 rs6904033 19 10.7 19 13.2 0.486 0.486 0.60 0.700.25 roh139 rs1321506 11 6.2 7 4.9 f 0.636 1.40 1.30 0.18 roh140rs6914527 20 14.4 6 4.2 5.36 0.021 0.70 1.20 0.32 roh141 rs10498827 3519.7 31 21.5 0.17 0.680 1.20 1.30 0.15 roh142 rs1340960 8 4.5 4 2.8 f0.558 1.40 1.10 0.10 roh143 rs6901402 16 9.0 7 4.9 2.045 0.153 1.30 1.700.15 roh144 rs1341230 27 15.2 18 12.5 0.472 0.492 0.40 1.00 0.28 roh145rs581803 14 7.9 14 9.7 0.346 0.557 1.60 1.20 0.10 roh146 rs2787892 2312.9 14 9.7 0.801 0.371 0.80 1.40 0.00 roh147 rs7754131 20 11.2 15 10.40.055 0.814 1.20 1.20 0.40 roh148 rs9385056 8 4.5 8 5.6 f 0.798 0.500.70 0.30 roh149 rs10456939 16 9.0 9 6.3 0.834 0.361 2.80 1.50 0.60roh150 rs9398971 17 9.6 10 6.9 0.704 0.402 2.00 0.80 0.65 roh151rs362868 18 10.1 16 11.1 0.084 0.772 1.70 3.10 0.62 roh152 rs6456234 126.7 7 4.9 f 0.635 1.80 1.10 0.32 roh153 rs6979640 10 5.6 8 5.6 f 1.0000.80 0.60 0.30 roh154 rs10230084 10 5.6 7 4.9 f 0.808 0.40 0.75 0.65roh155 ? 18 10.1 6 4.2 4.08 0.043 0.90 0.80 0.20 roh156 rs7384477 10 5.66 4.2 f 0.614 0.25 1.00 0.09 roh157 rs10486873 12 6.7 5 3.5 f 0.219 2.601.25 0.09 roh158 rs2732778 14 7.9 8 5.6 f 0.508 0.70 0.80 0.18 roh159rs1089468 14 7.9 5 3.5 f 0.152 0.60 1.00 0.38 roh160 rs7793335 16 9.0 128.3 0.043 0.836 1.00 2.50 0.58 roh161 rs17533951 40 22.5 25 17.4 1.2910.256 1.70 2.70 0.60 roh162 rs3808142 20 11.2 9 6.3 2.415 0.120 1.701.00 0.22 roh163 rs322740 14 7.9 6 4.2 f 0.245 1.30 1.00 0.20 roh164rs6972323 18 10.1 11 7.6 0.594 0.441 1.80 1.70 0.32 roh165 rs10046784 105.6 8 5.6 f 1.000 0.70 0.60 0.22 roh166 rs12544785 18 10.1 27 18.8 4.940.026 1.80 1.25 0.28 roh167 rs11777887 8 4.5 6 4.2 f 1.000 0.70 0.250.48 roh168 rs6586877 15 8.4 11 7.6 0.067 0.796 1.25 2.50 0.68 roh169rs1029340 28 15.7 21 14.6 0.081 0.776 0.90 0.75 0.20 roh170 rs1705227014 7.9 4 2.8 f 0.054 0.50 4.80 0.12 roh171 rs1981322 56 31.5 41 28.50.338 0.561 0.60 2.80 0.42 roh172 rs2360804 116 65.2 77 53.5 4.535 0.0333.90 2.00 0.90 roh173 rs16922281 20 11.2 5 3.5 6.7 0.010 1.60 1.40 0.22roh174 rs16926137 11 6.2 15 10.4 1.925 0.165 1.80 2.40 0.35 roh175rs4739071 15 8.4 9 6.3 0.547 0.460 2.20 1.40 0.45 roh176 rs16076 9 5.1 64.2 f 0.795 0.80 1.25 0.15 roh177 rs16912447 13 7.3 9 6.3 f 0.825 1.802.20 0.48 roh178 ? 11 6.2 11 7.6 f 0.660 0.80 1.15 0.20 roh179 rs168144413 7.3 4 2.8 f 0.083 1.80 1.10 0.42 roh180 rs2339228 15 8.4 8 5.6 0.990.320 1.70 1.50 0.40 roh181 rs16875331 12 6.7 6 4.2 f 0.343 0.75 0.800.60 roh182 rs3911267 26 14.6 23 16.0 0.115 0.734 2.25 1.80 0.52 roh183rs6986302 8 4.5 6 4.2 f 1.000 0.00 1.25 0.52 roh184 rs16892921 9 5.1 85.6 f 1.000 2.40 1.50 0.20 roh185 rs11786178 11 6.2 12 8.3 0.557 0.4562.25 1.75 0.09 roh186 rs1519856 9 5.1 9 6.3 f 0.808 1.00 0.80 0.15roh187 rs1355913 10 5.6 7 4.9 f 0.808 0.60 0.70 0.18 roh188 rs7022766 42.2 11 7.6 f 0.031 1.70 1.10 0.50 roh189 rs7861200 14 7.9 11 7.6 0.0060.940 1.25 1.25 0.70 roh190 rs12235141 7 3.9 4 2.8 f 0.760 1.80 0.700.32 roh191 rs765510 17 9.6 16 11.1 0.211 0.646 0.50 1.40 0.28 roh192rs17753877 10 5.6 4 2.8 f 0.276 1.20 2.80 0.55 roh193 rs10813040 26 14.619 13.2 0.132 0.716 1.50 1.20 0.21 roh194 rs16916378 19 10.7 15 10.40.006 0.940 0.00 1.00 0.98 roh195 rs12346810 11 6.2 7 4.9 f 0.636 2.250.25 0.00 roh196 rs3847322 6 3.4 9 6.3 f 0.289 0.70 0.25 0.20 roh197rs11143927 7 3.9 6 4.2 f 1.000 0.70 1.80 0.48 roh198 rs2011075 17 9.6 85.6 1.774 0.183 1.50 0.60 0.28 roh199 rs419574 23 12.9 7 4.9 6.121 0.0131.80 1.25 0.50 roh200 rs4336667 12 6.7 7 4.9 f 0.635 0.80 1.75 0.10roh201 rs603315 15 8.4 16 11.1 0.659 0.417 0.40 1.20 0.40 roh202rs7031853 12 6.7 7 4.9 f 0.635 2.70 1.80 0.50 roh203 rs9783219 9 5.1 53.5 f 0.589 0.40 2.00 0.65 roh204 rs11013273 19 10.7 16 11.1 0.016 0.9001.00 4.00 0.75 roh205 rs10828575 17 9.6 27 18.8 5.71 0.017 1.10 1.500.50 roh206 rs7068899 9 5.1 10 6.9 f 0.487 0.00 0.50 0.40 roh207rs748375 12 6.7 6 4.2 f 0.343 1.75 0.75 0.55 roh208 rs2754428 18 10.1 128.3 0.298 0.585 2.10 1.70 0.00 roh209 rs754618 30 16.9 16 11.1 2.1440.143 0.50 1.40 0.25 roh210 rs17176921 8 4.5 8 5.6 f 0.798 0.40 0.800.22 roh211 rs3011759 9 5.1 5.0 3.5 f 0.589 0.25 0.70 0.20 roh212rs1876328 10 5.6 5 3.5 f 0.433 0.80 1.40 0.18 roh213 rs7095049 48 27.026 18.1 3.571 0.059 2.00 1.75 0.48 roh214 rs1199094 9 5.1 12 8.3 f 0.2621.60 1.25 0.32 roh215 rs11006640 12 6.7 10 6.9 f 1.000 0.60 1.00 0.10roh216 rs2170005 11 6.2 4 2.8 f 0.188 0.25 0.60 0.09 roh217 rs1099593323 12.9 15 10.4 0.48 0.489 1.50 3.40 0.35 roh218 rs10762210 20 11.2 96.3 2.415 0.120 1.70 2.10 0.68 roh219 rs2675671 31 17.4 18 12.5 1.4910.222 3.00 2.70 0.35 roh220 rs10762739 22 12.4 13 9.0 0.912 0.340 0.600.90 0.15 roh221 rs1041626 34 19.1 24 16.7 0.319 0.572 1.90 0.90 0.35roh222 rs11201640 28 15.7 13 9.0 3.218 0.073 0.60 1.20 0.00 roh223rs4529840 32 18.0 18 12.5 1.821 0.177 2.70 0.70 0.50 roh224 rs2105010 169.0 13 9.0 0 0.990 0.60 0.80 0.41 roh225 rs2683658 35 19.7 33 22.9 0.5060.477 1.10 2.00 0.60 roh226 rs11193085 12 6.7 2 1.4 f 0.025 0.70 1.250.26 roh227 rs1441274 9 5.1 9 6.3 f 0.808 1.00 0.50 0.20 roh228rs11194172 10 5.6 11 7.6 f 0.502 0.70 0.70 1.40 roh229 rs11194677 9 5.19 6.3 f 0.808 0.70 1.25 0.40 roh230 rs7096937 16 9.0 22 15.3 3.025 0.0821.80 1.50 0.38 roh231 rs10490989 13 7.3 10 6.9 0.015 0.901 1.80 2.400.52 roh232 rs11199240 6 3.4 12 8.3 f 0.085 0.40 1.20 0.32 roh233rs10788165 8 4.5 5 3.5 f 0.779 0.00 0.75 0.25 roh234 rs10767461 14 7.9 85.6 f 0.508 0.80 0.80 0.38 roh235 rs1491799 9 5.1 6 4.2 f 0.795 0.401.10 0.45 roh236 rs2207073 17 9.6 9 6.3 1.168 0.280 0.25 0.40 0.10roh237 rs587876 17 9.6 11 7.6 0.366 0.545 0.80 0.50 0.38 roh238rs10501219 59 33.1 39 27.1 1.382 0.240 1.10 5.10 0.45 roh239 rs150852312 6.7 11 7.6 0.097 0.756 1.50 0.80 0.52 roh240 rs16938306 13 7.3 4 2.8f 0.083 0.80 1.25 0.20 roh241 rs10501329 61 34.3 48 33.3 0.031 0.8602.30 1.75 0.70 roh242 rs1613887 26 14.6 24 16.7 0.258 0.612 1.20 0.700.00 roh243 rs7940789 25 14.0 20 13.9 0.002 0.968 0.75 1.70 0.15 roh244rs1286289 21 11.8 16 11.1 0.037 0.848 0.50 2.00 0.00 roh245 rs633568 95.1 7 4.9 f 1.000 0.75 1.10 0.30 roh246 rs10830207 20 11.2 12 8.3 0.7490.387 1.00 0.75 0.30 roh247 rs10830716 17 9.6 15 10.4 0.067 0.796 1.301.30 0.38 roh248 rs7945975 7 3.9 13 9.0 f 0.067 0.00 0.40 0.10 roh249rs1792622 10 5.6 9 6.3 f 0.817 0.25 2.25 0.36 roh250 rs11225877 14 7.9 00.0 f 0.000 0.25 1.30 0.25 roh251 rs638266 38 21.3 23 16.0 1.498 0.2211.75 1.25 0.72 roh252 rs17115275 12 6.7 5 3.5 f 0.219 0.25 0.70 0.12roh253 rs956959 26 14.6 14 9.7 1.746 0.186 0.25 1.25 0.35 roh254rs7297320 7 3.9 7 4.9 f 0.786 1.90 1.80 0.58 roh255 rs11049731 4 2.2 106.9 f 0.053 0.00 0.30 0.08 roh256 rs16906504 6 3.4 10 6.9 f 0.197 0.800.20 0.25 roh257 rs11053146 7 3.9 10 6.9 f 0.316 1.10 0.60 0.58 roh258rs7486293 18 10.1 14 9.7 0.014 0.907 1.90 2.00 0.25 roh259 rs1908592 147.9 12 8.3 0.024 0.878 1.40 1.10 0.18 roh260 rs17094772 7 3.9 11 7.6 f0.222 0.60 1.75 0.32 roh261 rs10161093 8 4.5 5 3.5 f 0.779 0.40 1.200.62 roh262 rs10875842 5 2.8 7 4.9 f 0.384 1.80 2.00 0.22 roh263rs711330 11 6.2 7 4.9 f 0.636 0.25 0.70 0.25 roh264 rs17122290 9 5.1 96.3 f 0.808 0.25 1.10 0.58 roh265 rs11173469 9 5.1 6 4.2 f 0.795 0.700.70 0.18 roh266 rs6581758 8 4.5 4 2.8 f 0.558 0.25 0.60 2.40 roh267rs11180138 11 6.2 11 7.6 f 0.660 1.80 0.70 0.68 roh268 rs4143624 16 9.010 6.9 0.448 0.503 2.24 1.40 4.40 roh269 rs10735441 14 7.9 9 6.3 0.3130.576 1.20 2.50 0.35 roh270 rs7977839 20 11.2 21 14.6 0.803 0.370 0.600.70 0.80 roh271 rs17014369 16 9.0 9 6.3 0.834 0.361 1.25 2.60 0.68roh272 rs17016387 42 23.6 35 24.3 0.022 0.882 0.70 1.50 0.50 roh273rs11106228 14 7.9 10 6.9 0.098 0.754 2.00 0.70 0.08 roh274 rs17026179 147.9 6 4.2 f 0.245 1.20 0.80 0.00 roh275 rs10850084 42 23.6 37 25.7 0.1890.663 1.10 1.80 0.22 roh276 rs11066960 11 6.2 6 4.2 f 0.464 0.40 0.400.18 roh277 rs4415922 14 7.9 12 8.3 0.024 0.878 1.20 1.75 0.52 roh278rs9283079 10 5.6 7 4.9 f 0.808 0.90 1.25 0.09 roh279 rs9537441 23 12.914 9.7 0.801 0.371 0.75 0.75 0.45 roh280 rs7992804 16 9.0 7 4.9 2.0450.153 1.50 2.50 0.25 roh281 rs12431035 7 3.9 9 6.3 f 0.441 1.20 1.000.00 roh282 rs1770325 10 5.6 8 5.6 f 1.000 1.10 1.40 0.22 roh283rs9560362 14 7.9 7 4.9 f 0.365 0.90 0.75 0.00 roh284 rs9516766 15 8.4 53.5 f 0.102 0.50 1.50 0.45 roh285 rs1957583 8 4.5 7 4.9 f 1.000 0.251.50 0.50 roh286 rs10150617 4 2.2 11 7.6 f 0.031 0.25 0.40 0.40 roh287rs12147034 21 11.8 16 11.1 0.037 0.848 0.60 2.10 0.38 roh288 rs1115836614 7.9 15 10.4 0.632 0.426 2.40 2.00 0.80 roh289 rs7144688 5 2.8 9 6.3 f0.171 1.60 2.10 0.68 roh290 rs17825846 13 7.3 5 3.5 f 0.152 1.10 1.200.42 roh291 rs12437164 86 48.3 47 32.6 8.068 0.005 2.50 2.75 0.99 roh292rs7359118 23 12.9 15 10.4 0.48 0.489 0.40 1.10 0.30 roh293 rs1892225 73.9 11 7.6 f 0.222 0.90 1.10 0.18 roh294 rs3784391 8 4.5 6 4.2 f 1.0001.10 1.30 0.65 roh295 rs11637483 31 17.4 17 11.8 1.975 0.160 1.60 3.200.90 roh296 rs4381535 42 23.6 23 16.0 2.871 0.090 1.80 2.50 0.70 roh297rs2445765 6 3.4 7 4.9 f 0.575 0.70 0.30 0.18 roh298 rs8034032 13 7.3 96.3 f 0.825 2.10 1.75 0.38 roh299 rs1073097 17 9.6 16 11.1 0.211 0.6460.70 0.60 0.10 roh300 rs4777180 18 10.1 12 8.3 0.298 0.585 1.60 2.601.25 roh301 rs16957968 29 16.3 19 13.2 0.602 0.438 2.20 2.80 0.78 roh302rs17382798 7 3.9 7 4.9 f 0.786 1.50 1.40 0.21 roh303 rs11635431 11 6.2 53.5 f 0.311 0.40 0.80 0.15 roh304 rs12595866 7 3.9 6 4.2 f 1.000 0.400.60 0.21 roh305 rs10500375 11 6.2 9 6.3 f 1.000 0.40 0.60 0.00 roh306rs8046716 38 21.3 21 14.6 2.434 0.119 0.90 4.25 0.35 roh307 rs13329873 95.1 8 5.6 f 1.000 1.50 0.30 0.10 roh308 rs4783573 29 16.3 23 16.0 0.0060.938 1.10 2.60 0.80 roh309 ? 7 3.9 6 4.2 f 1.000 1.30 1.10 0.10 roh310? 23 12.9 17 11.8 0.091 0.763 2.25 2.20 0.50 roh311 rs1518603 24 13.5 1510.4 0.703 0.402 1.80 1.20 0.60 roh312 rs7205794 11 6.2 5 3.5 f 0.3111.00 1.00 0.45 roh313 rs4796675 18 10.1 17 11.8 0.236 0.627 0.80 1.100.40 roh314 rs11570441 40 22.5 14 9.7 9.271 0.002 2.50 0.75 0.35 roh315rs9898730 14 7.9 15 10.4 0.632 0.426 1.70 0.70 0.28 roh316 rs9912513 2312.9 18 12.5 0.013 0.910 0.90 1.70 0.70 roh317 rs12948356 24 13.5 13 9.01.554 0.213 0.60 2.60 0.72 roh318 rs7235201 9 5.1 4 2.8 f 0.398 0.801.10 0.55 roh319 rs16946546 13 7.3 8 5.6 f 0.652 1.60 0.75 0.00 roh320rs1562995 18 10.1 12 8.3 0.298 0.585 0.40 1.50 0.32 roh321 rs16975303 158.4 1 0.7 f 0.001 2.25 1.60 0.24 roh322 rs610325 21 11.8 10 6.9 2.1550.142 0.60 0.80 0.10 roh323 rs11083005 16 9.0 16 11.1 0.401 0.527 1.250.70 0.38 roh324 rs1420766 17 9.6 16 11.1 0.211 0.646 0.70 0.40 0.10roh325 rs17069904 13 7.3 3 2.1 f 0.039 0.00 1.40 0.25 roh326 rs110854687 3.9 8 5.6 f 0.598 0.80 1.40 0.38 roh327 rs7252575 28 15.7 17 11.8 1.020.313 1.20 2.00 0.25 roh328 rs10412480 11 6.2 10 6.9 f 0.823 0.60 1.800.08 roh329 rs833915 7 3.9 5 3.5 f 1.000 0.80 0.80 0.42 roh330 rs74285325 14.0 32 22.2 3.654 0.056 2.50 1.75 0.40 roh331 rs6049605 9 5.1 6 4.2f 0.795 1.10 1.60 0.42 roh332 rs6015104 20 11.2 22 15.3 1.147 0.284 2.501.80 0.38 roh333 rs6071828 28 15.7 14 9.7 2.533 0.111 1.25 1.20 0.45roh334 ? 22 12.4 16 11.1 0.119 0.730 1.00 0.70 0.10 roh335 rs4811599 179.6 6 4.2 3.479 0.062 1.75 1.75 0.55 roh336 rs2829931 16 9.0 6 4.2 f0.119 1.10 1.50 0.20 roh337 rs8129810 24 13.5 22 15.3 0.209 0.647 2.242.25 0.58 roh338 rs12484740 14 7.9 15 10.4 0.632 0.426 1.60 2.00 0.30roh339 rs5998365 13 7.3 10 6.9 0.015 0.901 1.20 1.10 0.42 roh340rs17002946 16 9.0 9 6.3 0.834 0.361 0.90 1.30 0.30

SUPPLEMENTARY TABLE 2 Affy_ID dbSNP Chr band Position Gene P-valueSNP_A-2056719 rs2923062 8 q11.21 51441469 SNTG1 6.69E−03 SNP_A-2303509rs16914780 8 q11.21 51449609 SNTG1 6.69E−03 SNP_A-2193025 rs16914781 8q11.21 51450035 SNTG1 6.69E−03 SNP_A-4204516 rs4534138 8 q11.21 51451367SNTG1 6.69E−03 SNP_A-2281233 rs10957894 8 q11.21 51454425 SNTG1 7.99E−03SNP_A-2057710 rs4292700 8 q11.21 51455302 SNTG1 7.99E−03 SNP_A-1956376rs7823310 8 q11.21 51456091 SNTG1 7.99E−03 SNP_A-2095646 rs6473111 8q11.21 51458884 SNTG1 7.99E−03 SNP_A-2198909 rs7839253 8 q11.21 51459986SNTG1 7.99E−03 SNP_A-4282968 rs4524809 8 q11.21 51462851 SNTG1 7.99E−03SNP_A-1917516 rs4339654 8 q11.21 51463114 SNTG1 7.99E−03 SNP_A-1858682rs4529480 8 q11.21 51469016 SNTG1 7.99E−03 SNP_A-1961465 rs4563896 8q11.21 51473631 SNTG1 3.97E−03 SNP_A-2266190 rs7820992 8 q11.21 51473649SNTG1 3.97E−03 SNP_A-2206873 rs4242461 8 q11.21 51475032 SNTG1 1.78E−03SNP_A-2146318 rs7843301 8 q11.21 51498389 SNTG1 1.78E−03 SNP_A-4266939rs2062039 8 q11.21 51502012 SNTG1 1.78E−03 SNP_A-2150690 rs1481467 8q11.21 51506089 SNTG1 2.67E−03 SNP_A-4203395 rs9650165 8 q11.21 51506205SNTG1 2.53E−03 SNP_A-2150643 rs10957915 8 q11.21 51511311 SNTG1 2.53E−03SNP_A-2132611 rs10957916 8 q11.21 51511374 SNTG1 2.53E−03 SNP_A-2075720rs1471578 8 q11.21 51523063 SNTG1 1.70E−03 SNP_A-1895133 rs9987391 8q11.21 51523500 SNTG1 1.70E−03 SNP_A-4276525 rs4873147 8 q11.21 51524267SNTG1 1.70E−03 SNP_A-4277171 rs4873458 8 q11.21 51524300 SNTG1 1.70E−03SNP_A-4228253 rs10088756 8 q11.21 51528317 SNTG1 1.70E−03 SNP_A-1961356rs1383819 8 q11.21 51534019 SNTG1 3.73E−03 SNP_A-4217136 rs1904997 8q11.21 51541878 SNTG1 3.73E−03 SNP_A-4237065 rs4440649 8 q11.21 51542530SNTG1 1.78E−03 SNP_A-2022493 rs12547263 8 q11.21 51552222 SNTG1 1.78E−03SNP_A-1801379 rs1481472 8 q11.21 51557371 SNTG1 1.78E−03 SNP_A-1993218rs2392699 8 q11.21 51563239 SNTG1 1.78E−03 SNP_A-2265987 rs2467203 8q11.21 51605982 SNTG1 1.21E−03 SNP_A-2184475 ? 8 q11.21 51610161 SNTG11.21E−03 SNP_A-1874720 rs1542615 8 q11.21 51616502 SNTG1 1.21E−03SNp_A-1921640 rs2623207 8 q11.21 51620897 SNTG1 1.21E−03 SNP_A-2046087rs2623225 8 q11.21 51622219 SNTG1 1.21E−03 SNP_A-4254534 rs2625758 8q11.21 51624716 SNTG1 5.10E−04 SNP_A-2152914 rs2623224 8 q11.21 51624769SNTG1 3.28E−04 SNP_A-1923956 rs16915033 8 q11.21 51625180 SNTG1 7.57E−04SNP_A-2238756 rs10107280 8 q11.21 51631958 SNTG1 7.57E−04 SNP_A-2037049rs1483640 8 q11.21 51633485 SNTG1 1.81E−03 SNP_A-2293183 rs1351754 8q11.21 51651167 SNTG1 1.81E−03 SNP_A-1937391 rs1580413 8 q11.21 51651512SNTG1 1.81E−03 SNP_A-4253129 rs996166 8 q11.21 51657369 SNTG1 4.24E−03SNP_A-4207289 rs1483638 8 q11.21 51681895 SNTG1 2.81E−03 SNP_A-1825303rs6473253 8 q11.21 51684525 SNTG1 2.81E−03 SNP_A-2153675 rs6998737 8q11.21 51693370 SNTG1 2.81E−03 SNP_A-2094331 rs16915106 8 q11.2151699950 SNTG1 2.81E−03 SNP_A-4206075 rs11991826 8 q11.21 51701087 SNTG12.81E−03 SNP_A-1933938 rs16915112 8 q11.21 51701435 SNTG1 2.81E−03SNP_A-4266940 rs1384830 8 q11.21 51707146 SNTG1 2.81E−03 SNP_A-1993221rs10216995 8 q11.21 51712398 SNTG1 2.81E−03 SNP_A-1791334 rs4401874 8q11.21 51719839 SNTG1 4.24E−03 SNP_A-2062612 rs1384831 8 q11.21 51723458SNTG1 4.24E−03 SNP_A-1993222 rs10110909 8 q11.21 51727199 SNTG1 9.48E−03SNP_A-2264825 rs6473289 8 q11.21 51756441 SNTG1 6.17E−03 SNP_A-2151001rs1396377 8 q11.21 51756680 SNTG1 6.17E−03 SNP_A-1914476 rs6473290 8q11.21 51759364 SNTG1 6.17E−03 SNP_A-2086177 rs7016914 8 q11.21 51780168SNTG1 6.17E−03 SNP_A-2265202 ? 8 q11.21 51793164 SNTG1 6.17E−03SNP_A-1902908 rs1911832 8 q11.21 51797066 SNTG1 6.17E−03 SNP_A-1905567rs6985954 8 q11.21 51798428 SNTG1 2.81E−03 SNP_A-2081526 rs6473320 8q11.21 51804559 SNTG1 2.81E−03 SNP_A-1993223 rs906656 8 q11.21 51805005SNTG1 2.81E−03 SNP_A-4259350 rs11986411 8 q11.21 51816608 SNTG1 2.81E−03SNP_A-2013388 rs7831651 8 q11.21 51859645 SNTG1 4.24E−03 SNP_A-1958710rs7832680 8 q11.21 51859663 SNTG1 4.24E−03 SNP_A-1819627 rs7832799 8q11.21 51859715 SNTG1 4.24E−03 SNP_A-2126502 ? 8 q11.21 51866630 SNTG14.24E−03 SNP_A-4295444 rs7008324 8 q11.21 51883526 intergenic 2.81E−03SNP_A-4199849 rs1484126 8 q11.21 51884347 intergenic 2.81E−03SNP_A-1882648 rs1484127 8 q11.21 51888207 intergenic 2.81E−03SNP_A-2260759 rs1484128 8 q11.21 51888421 intergenic 2.81E−03SNP_A-1855713 rs6473406 8 q11.21 51900282 intergenic 2.81E−03SNP_A-2258910 rs1484129 8 q11.21 51900540 intergenic 2.81E−03SNP_A-4234491 rs2392742 8 q11.21 51932422 intergenic 2.81E−03SNP_A-2147522 rs4520181 8 q11.21 51932442 intergenic 1.85E−03SNP_A-2083927 rs7013653 8 q11.21 51933484 intergenic 1.85E−03SNP_A-1783958 rs4633069 8 q11.21 51939038 intergenic 1.85E−03SNP_A-2295301 rs1601194 8 q11.21 51941043 intergenic 1.85E−03SNP_A-4245626 rs975382 8 q11.21 51945468 intergenic 1.85E−03SNP_A-1791182 rs10283050 8 q11.21 51949988 intergenic 1.85E−03SNP_A-4243596 rs10283046 8 q11.21 51950419 intergenic 1.85E−03SNP_A-4271145 rs7016107 8 q11.21 51951872 intergenic 1.85E−03SNP_A-1817118 rs10102886 8 q11.21 51968128 intergenic 1.85E−03SNP_A-1868040 rs6987928 8 q11.21 51977243 intergenic 1.85E−03SNP_A-2045171 rs11994633 8 q11.21 51979461 intergenic 1.85E−03SNP_A-4206004 rs6473486 8 q11.21 51979598 intergenic 1.85E−03SNP_A-1993224 rs10504109 8 q11.21 51997438 intergenic 1.85E−03SNP_A-1880357 rs13281139 8 q11.21 52006606 intergenic 1.85E−03SNP_A-1920800 rs1159997 8 q11.21 52021786 intergenic 4.14E−03SNP_A-4290353 rs7837741 8 q11.21 52027657 intergenic 4.14E−03SNP_A-2204830 rs1905526 8 q11.21 52032418 intergenic 4.14E−03SNP_A-2291000 rs6989442 8 q11.21 52036135 intergenic 4.14E−03SNP_A-2260772 rs9969399 8 q11.21 52037226 intergenic 4.14E−03SNP_A-1883909 rs1484130 8 q11.21 52045960 intergenic 4.14E−03SNP_A-1896767 rs2168331 8 q11.21 52070083 intergenic 4.14E−03SNP_A-4202203 rs2219209 8 q11.21 52079813 intergenic 4.14E−03SNP_A-1937329 rs2392765 8 q11.21 52079874 intergenic 4.14E−03SNP_A-1920731 rs6473561 8 q11.21 52080057 intergenic 9.11E−03SNP_A-2064652 rs16915710 8 q11.21 52091409 intergenic 6.17E−03SNP_A-4196531 rs7009881 8 q11.21 52092215 intergenic 6.17E−03SNP_A-2024615 rs10958238 8 q11.21 52109252 intergenic 6.17E−03SNP_A-1826896 rs10106393 8 q11.21 52120991 intergenic 6.17E−03SNP_A-2060292 rs6473574 8 q11.21 52122112 intergenic 6.17E−03SNP_A-4222443 rs17728090 8 q11.21 52132300 intergenic 6.17E−03SNP_A-1938600 rs6993652 8 q11.21 52154155 intergenic 6.17E−03SNP_A-1792544 rs11192943 10 q25.1 108287891 intergenic 6.12E−03SNP_A-2021825 rs7088535 10 q25.1 108288081 intergenic 6.12E−03SNP_A-1782767 rs17297851 10 q25.1 108289414 intergenic 6.12E−03SNP_A-2311304 rs17297858 10 q25.1 108289455 intergenic 6.12E−03SNP_A-2028442 rs11192958 10 q25.1 108317321 intergenic 6.12E−03SNP_A-2053519 rs12359404 10 q25.1 108324179 SORCS1 6.12E−03SNP_A-2004985 rs10491050 10 q25.1 108325998 SORCS1 6.12E−03SNP_A-2048295 rs11192967 10 q25.1 108329322 SORCS1 6.12E−03SNP_A-1830517 rs11192968 10 q25.1 108330433 SORCS1 1.50E−03SNP_A-1940703 rs4917477 10 q25.1 108336217 SORCS1 2.40E−03 SNP_A-1819847rs17120993 10 q25.1 108337180 SORCS1 2.40E−03 SNP_A-2251198 rs1712102310 q25.1 108342175 SORCS1 2.40E−03 SNP_A-1956347 rs11814145 10 q25.1108345833 SORCS1 2.40E−03 SNP_A-2048623 rs1269918 10 q25.1 108345864SORCS1 2.40E−03 SNP_A-2050923 rs11817694 10 q25.1 108348488 SORCS12.40E−03 SNP_A-1951360 rs11192973 10 q25.1 108353452 SORCS1 2.40E−03SNP_A-4214438 rs11192974 10 q25.1 108354288 SORCS1 2.40E−03SNP_A-4214439 rs11817663 10 q25.1 108354299 SORCS1 2.40E−03SNP_A-2004989 rs10884335 10 q25.1 108354793 SORCS1 2.40E−03SNP_A-1888019 rs6584758 10 q25.1 108359502 SORCS1 2.40E−03 SNP_A-2153850rs10884337 10 q25.1 108366461 SORCS1 2.40E−03 SNP_A-1922461 rs1322006 10q25.1 108370516 SORCS1 2.40E−03 SNP_A-2246290 rs1322005 10 q25.1108370669 SORCS1 2.40E−03 SNP_A-4222780 rs7074484 10 q25.1 108371247SORCS1 2.40E−03 SNP_A-2035855 rs7914387 10 q25.1 108371398 SORCS12.40E−03 SNP_A-2104084 rs7901090 10 q25.1 108382032 SORCS1 2.40E−03SNP_A-2291700 rs11192994 10 q25.1 108398096 SORCS1 2.40E−03SNP_A-2312317 rs11192997 10 q25.1 108400332 SORCS1 2.40E−03SNP_A-1815743 rs11192998 10 q25.1 108400575 SORCS1 2.40E−03SNP_A-2050336 rs11193000 10 q25.1 108404270 SORCS1 2.40E−03SNP_A-1851132 rs12254438 10 q25.1 108409046 SORCS1 2.40E−03SNP_A-2196714 rs7095966 10 q25.1 108410576 SORCS1 2.40E−03 SNP_A-2041150rs11193005 10 q25.1 108411130 SORCS1 2.40E−03 SNP_A-1852117 rs1159822310 q25.1 108411946 SORCS1 2.40E−03 SNP_A-1869058 rs9633679 10 q25.1108412110 SORCS1 2.40E−03 SNP_A-2258251 rs11193007 10 q25.1 108414751SORCS1 2.40E−03 SNP_A-2001412 rs821931 10 q25.1 108427629 SORCS12.40E−03 SNP_A-2233066 rs821925 10 q25.1 108432009 SORCS1 2.40E−03SNP_A-2157313 rs821943 10 q25.1 108432517 SORCS1 2.40E−03 SNP_A-2115676rs12256633 10 q25.1 108433366 SORCS1 2.40E−03 SNP_A-4250999 rs821940 10q25.1 108434959 SORCS1 2.40E−03 SNP_A-4272241 rs821934 10 q25.1108438994 SORCS1 2.40E−03 SNP_A-1921494 rs821958 10 q25.1 108445133SORCS1 2.40E−03 SNP_A-2236831 rs12243064 10 q25.1 108464605 SORCS12.40E−03 SNP_A-1785958 rs12250100 10 q25.1 108464855 SORCS1 2.40E−03SNP_A-2086159 rs12267167 10 q25.1 108466097 SORCS1 2.40E−03SNP_A-1898273 rs10884341 10 q25.1 108469639 SORCS1 2.40E−03SNP_A-2255102 rs11193022 10 q25.1 108470389 SORCS1 2.40E−03SNP_A-4279933 rs1040871 10 q25.1 108474359 SORCS1 2.40E−03 SNP_A-2069915rs1358874 10 q25.1 108474505 SORCS1 2.40E−03 SNP_A-1896037 rs10786967 10q25.1 108483941 SORCS1 2.40E−03 SNP_A-1886734 rs10884345 10 q25.1108484098 SORCS1 2.40E−03 SNP_A-2132861 rs7903481 10 q25.1 108489892SORCS1 2.40E−03 SNP_A-4245944 rs10884350 10 q25.1 108490065 SORCS12.40E−03 SNP_A-4239956 rs10458732 10 q25.1 108490394 SORCS1 2.40E−03SNP_A-2004997 rs9325521 10 q25.1 108490722 SORCS1 2.40E−03 SNP_A-2004999rs1890457 10 q25.1 108511556 SORCS1 2.40E−03 SNP_A-2005001 rs999776 10q25.1 108516800 SORCS1 2.40E−03 SNP_A-2115027 rs12771665 10 q25.1108521546 SORCS1 2.40E−03 SNP_A-2218082 rs2484972 10 q25.1 108521598SORCS1 2.40E−03 SNP_A-1785362 rs11193042 10 q25.1 108521694 SORCS12.40E−03 SNP_A-4247707 rs945598 10 q25.1 108522614 SORCS1 2.40E−03SNP_A-4254338 rs12779808 10 q25.1 108522767 SORCS1 2.40E−03SNP_A-4282066 rs878182 10 q25.1 108523116 SORCS1 2.40E−03 SNP_A-2005003rs10509821 10 q25.1 108524996 SORCS1 2.40E−03 SNP_A-4268792 rs1050982210 q25.1 108525418 SORCS1 2.40E−03 SNP_A-1802885 rs2245123 10 q25.1108543204 SORCS1 2.40E−03 SNP_A-1820891 rs2255917 10 q25.1 108546112SORCS1 2.40E−03 SNP_A-1858009 rs2486154 10 q25.1 108549689 SORCS12.40E−03 SNP_A-2283854 rs4917487 10 q25.1 108550789 SORCS1 2.40E−03SNP_A-2154229 rs12248379 10 q25.1 108551998 SORCS1 2.40E−03SNP_A-4201161 rs11193059 10 q25.1 108562383 SORCS1 2.40E−03SNP_A-1843438 rs1538417 10 q25.1 108573589 SORCS1 2.40E−03 SNP_A-4202792rs11597875 10 q25.1 108580272 SORCS1 2.40E−03 SNP_A-2084521 rs7087219 10q25.1 108611655 SORCS1 2.40E−03 SNP_A-4216596 rs874887 10 q25.1108613957 SORCS1 2.40E−03 SNP_A-2188906 rs1336615 10 q25.1 108616599SORCS1 3.86E−03 SNP_A-2081598 rs11193085 10 q25.1 108623596 SORCS13.86E−03

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In view of the above, it will be seen that the several advantages of theinvention are achieved and other advantages attained.

As various changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

All references cited in this specification are hereby incorporated byreference. The discussion of the references herein is intended merely tosummarize the assertions made by the authors and no admission is madethat any reference constitutes prior art. Applicants reserve the rightto challenge the accuracy and pertinence of the cited references.

1. A method of determining the relative risk of a human subject formanifesting schizophrenia, the method comprising determining thepresence of a first run of homozygosity (ROH) in the genome of thesubject, wherein the presence of the first ROH indicates the subject hasan increased risk for manifesting schizophrenia over a subject nothaving the first ROH, wherein the first ROH is a series of consecutivesingle nucleotide polymorphism (SNP) positions that are homozygous inthe subject from one of roh250, roh321, roh314, roh52, roh15, roh129,roh291, roh55, or roh173 as defined in Table
 2. 2. The method of claim1, wherein the first ROH is a series of at least 50 consecutivehomozygous SNP positions.
 3. The method of claim 1, wherein the firstROH is a series of at least 100 consecutive homozygous SNP positions. 4.The method of claim 1, wherein the first ROH is a series of all of theSNP positions that are homozygous in the subject from roh250, roh321,roh314, roh52, roh15, roh129, roh291, roh55, or roh173.
 5. The method ofclaim 1, the method further comprising determining the presence of asecond ROH in the genome of the subject, wherein the second ROH is fromone of roh250, roh321, roh314, roh52, roh15, roh129, roh291, roh55, orroh173 that is different from the first ROH, wherein the presence of thesecond ROH indicates the subject has an increased risk for manifestingschizophrenia over a subject not having the second ROH.
 6. The method ofclaim 1, wherein the presence of roh250 is determined.
 7. The method ofclaim 1, wherein positions in the genome of the subject corresponding toeach of roh250, roh321, roh314, roh52, roh15, roh129, roh291, roh55, androh173 are evaluated for the consecutive homozygous SNP positions,wherein an increasing number of ROHs present in the subject indicates anincreasing risk in the subject for manifesting schizophrenia.
 8. Themethod of claim 1, wherein the subject is an embryo or fetus.
 9. Themethod of claim 8, wherein the subject is an embryo.
 10. The method ofclaim 8, wherein the subject is a fetus.
 11. A method of determining therelative risk of a human subject for manifesting schizophrenia, themethod comprising determining whether the subject has a run ofhomozygosity (ROH) that contains at least 80% of the SNPs in at leastone of the three locations identified in Supplementary Table 2 ascorrelated with schizophrenia, wherein a subject having an ROH thatcontains at least 80% of the SNPs in at least one of the three locationsidentified in Supplementary Table 2 has an increased risk formanifesting schizophrenia over a subject not having such an ROH.
 12. Themethod of claim 11, comprising determining whether the subject has anROH that contains at least 90% of the SNPs in at least one of the threelocations identified in Supplementary Table 2 as correlated withschizophrenia, wherein a subject having an ROH that contains at least90% of the SNPs in at least one of the three locations identified inSupplementary Table 2 has an increased risk for manifestingschizophrenia over a subject not having such an ROH.
 13. The method ofclaim 11, comprising determining whether the subject has an ROH thatcontains 100% of the SNPs in at least one of the three locationsidentified in Supplementary Table 2 as correlated with schizophrenia,wherein a subject having an ROH that contains 100% of the SNPs in atleast one of the three locations identified in Supplementary Table 2 hasan increased risk for manifesting schizophrenia over a subject nothaving such an ROH.
 14. A method of screening a human embryo in vitrofor the risk of becoming a human manifesting schizophrenia, the methodcomprising determining the presence of a first run of homozygosity (ROH)in the genome of the embryo, wherein the presence of the first ROHindicates the embryo has an increased risk for manifesting schizophreniaover an embryo not having the first ROH, wherein the first ROH is aseries of consecutive single nucleotide polymorphism (SNP) positionsthat are homozygous in the subject from one of roh250, roh321, roh314,roh52, roh15, roh129, roh291, roh55, or roh173 as defined in Table 2.15. The method of claim 14, wherein positions in the genome of theembryo corresponding to each of roh250, roh321, roh314, roh52, roh15,roh129, roh291, roh55, and roh173 are evaluated for the consecutivehomozygous SNP positions, wherein an increasing number of ROHs presentin the subject indicates an increasing risk in the subject formanifesting schizophrenia.
 16. A method of identifying a singlenucleotide polymorphism (SNP) variant affecting the risk of a humansubject for manifesting schizophrenia, the method comprising identifyinga run of homozygosity (ROH) present more often in a first population ofindividuals having schizophrenia than in a second population ofindividuals not having schizophrenia, then identifying a singlenucleotide polymorphism (SNP) within the ROH or within 500 kB of theROH, where a first variant of the SNP is present in the first populationmore often than in the second population, wherein the presence of thefirst variant of the SNP in a subject indicates that the subject has agreater risk for manifesting schizophrenia than the absence of the firstvariant, wherein an ROH is a series of consecutive known SNP positionsthat are homozygous in the genome of an individual.
 17. The method ofclaim 16, wherein the ROH is one of roh250, roh321, roh314, roh52,roh15, roh129, roh291, roh55, or roh173 as defined in Table
 2. 18. Themethod of claim 16, wherein the SNP is within an open reading frame. 19.The method of claim 18, wherein the open reading frame is in a geneselected from the group consisting of DYNC2H1, PIK3C3, CRHR1, IMP5,MAPT, STH, KIAA1267, LRRC37A, ARL17, LRRC37A2, NSF, WNT3, WNT9B, GOSR2,RPRML, CDC27, CHN1, ATF2, ATP5GS3, DUSP12, ATF6, OLFML2B, NOS1AP, SGCD,MRPL22, GPHN, C14orf54, MPP5, ATP6V1D, EIF2S1, PLEK2, GULP1, DIRC1,COL3A1, COL5A2, WDR75, SLC40A1, NS3TP1, ASNSD1, ANKAR, OSGEPL1, ORMDL1,PMS1, GDF8, and IMPAD1.
 20. A method of determining the relative risk ofa human subject for manifesting schizophrenia, the method comprisingdetermining whether the subject has a SNP genotype associated withschizophrenia as identified by the method of claim 16, wherein a subjectwith the SNP genotype has an increased risk for manifestingschizophrenia over a subject with a different genotype.
 21. A method ofscreening for a compound that may affect schizophrenia, the methodcomprising determining whether the compound affects expression oractivity of a gene selected from the group consisting of DYNC2H1, CRHR1,IMP5, MAPT, STH, KIAA1267, LRRC37A, ARL17, LRRC37A2, WNT3, WNT9B, GOSR2,RPRML, CDC27, CHN1, ATP5GS3, DUSP12, ATF6, OLFML2B, SGCD, MRPL22, GPHN,C14orf54, MPP5, ATP6V1D, EIF2S1, PLEK2, GULP1, DIRC1, COL3A1, COL5A2,WDR75, SLC40A1, NS3TP1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, PMS1, GDF8,IMPAD1, SNTG1 and SORCS1, wherein a compound that affects expression oractivity of the gene may affect schizophrenia.
 22. The method of claim21, wherein the gene is MAPT, GPHN, SNTG1 or SORCS1.
 23. The method ofclaim 21, wherein the compound is contacted with a product of the genethen the activity of the gene product is measured.
 24. The method ofclaim 23, wherein the compound is contacted with the product of the genein vitro.
 25. The method of claim 23, wherein the compound is contactedwith a cell that expresses the product of the gene such that thecompound contacts the product of the gene.
 26. The method of claim 21,wherein the compound is contacted with a cell that is capable ofexpressing the gene, and expression of the gene is measured and comparedto expression of the gene in a cell that is not contacted with thecompound.
 27. The method of claim 21, wherein the compound isadministered to a mammal and activity of a product of the gene ismeasured and compared to activity of the product of the gene in a mammalthat is not administered the compound.
 28. The method of claim 21,wherein the compound is administered to a mammal and expression of thegene is measured and compared to expression of the gene in a mammal thatis not administered the compound.